The HBB NM_000518.5:c.93-21G>A (NP_000509.1:p.?) intronic variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Patient-derived erythroid cells showed approximately 90% reduced HBB production and aberrant mRNA retaining a 19-nucleotide intronic fragment with an in-frame stop codon. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Hemoglobinopathy Variant Curation Expert Panel, ClinGen; ClinVar ID 15454).
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.HBB encodes the beta-globin protein, one of the two types of chains that combine with alpha-globin to form adult hemoglobin, which carries oxygen in the blood. Abnormal or absent beta-globin is associated with sickle cell disease and beta-thalassemia. HBB has no established cancer role.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at strong: patient-derived erythroid cells showed approximately 90% reduced HBB production and aberrant mRNA retaining a 19-nucleotide intronic fragment with an in-frame stop codon.
Met: Iranian cases had 3/100 variant chromosomes versus 12/6,062 Middle Eastern gnomAD alleles, yielding OR 15.59 (95% CI 4.33-56.14), above 5.0 with CI excluding 1.0.
Met at supporting strength: the exact variant occurred on a beta-thalassemia allele in a patient doubly heterozygous with pathogenic Hb Lepore, supporting trans phase.
Met at supporting: intronic SpliceAI max delta 0.442 exceeds the PP3 supporting threshold of >=0.2 but not the moderate threshold of >=0.5.
Met: the exact variant has a three-star ClinVar Pathogenic classification from the ClinGen Hemoglobinopathy Variant Curation Expert Panel.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 and PS4 at strong strength satisfy the generic ACMG/AMP rule for two strong pathogenic criteria, with PM3, PP3, and PP5 also supporting.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 197 / 1,608,186 alleles. Recorded AF 0.000122498. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000148758; MAF= 0.01488%, 42/282338 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0002872; MAF= 0.02872%, 37/128830 alleles, homozygotes = 0); grpmax FAF= 0.0002203.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.442. Refer to the recorded PP3/BP4 rationale for interpretation.
30 Pathogenic · 2 pathogenic · 2 Likely pathogenic · 1 Likely Pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 6 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the three requested consequence criteria, the variant is an intronic single-nucleotide substitution: PVS1, PM4, and BP3 are each outside the named variant types or locations of their generic ACMG/AMP definitions.
Generic ACMG/AMP rules govern because the ClinGen Hemoglobinopathy HBB expert-panel specification is listed but has no released criteria.
PS4 is met quantitatively from the Iranian case cohort versus matched-ancestry gnomAD v4.1 controls; PP5 is met from the exact-variant expert-panel ClinVar classification.
PP4 and BP5 remain not assessed because patient-specific phenotype/family-history and alternate-molecular-basis evidence are unavailable; BP6 is not met because the expert-panel classification is Pathogenic rather than benign.
The variant is intronic, so PP3 and BP4 were evaluated exclusively through the SpliceAI path; REVEL and protein-impact prediction were not applicable.
SpliceAI maximum delta 0.442 meets PP3 supporting but exceeds the BP4 no-impact threshold, while BP7 is not applicable because the variant is not synonymous.
Population evidence does not meet BA1, BS1, BS2, or PM2: the variant is rare but its filtering FAF exceeds the PM2 cutoff and remains far below the BA1 and BS1 thresholds, with no healthy homozygotes observed.
No criteria match.
PS3 is met at strong strength. PMID:29700171 directly studied HBB IVSI-110(G>A), corresponding to NM_000518.5:c.93-21G>A, in a humanized erythroid-cell model and primary CD34+ hematopoietic stem/progenitor cells from four homozygous patients. The study reported approximately 90% reduction of HBB/beta-globin production and aberrant HBB mRNA retaining a 19-nucleotide intronic fragment with an in-frame stop codon. Variant-specific RNA quantification, HBB immunoblotting, erythroid differentiation and hemoglobinization microscopy, and reversed-phase HPLC were concordant; rescue with mutation-specific shRNA or gene addition increased HBB protein and improved erythroid/hemoglobin-related measurements. This is direct, biologically relevant RNA/protein and cellular functional evidence of a damaging splicing effect, with patient-derived material and orthogonal readouts. No BS3 evidence is present: the reported normal in-vitro transcription result in an older paper does not assess splicing or protein function and therefore does not show absence of a damaging effect.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The exact variant was reported in 50 Iranian beta-thalassemia-intermedia patients: 3.0% of 100 analyzed chromosomes, corresponding to 3 variant and 97 non-variant chromosomes. As a matched-ancestry population comparison, gnomAD v4.1 Middle Eastern controls had 12/6,062 variant alleles and 6,050 non-variant alleles. I computed the case-control odds ratio as (3x6050)/(97x12)=15.59, with a Woolf 95% CI of 4.33-56.14. The governing ACMG threshold is OR >5.0 with a confidence interval that does not include 1.0; explicit comparison: 15.59 > 5.0? yes, and 4.33-56.14 includes 1.0? no. Therefore PS4 is met. The literature_pass PS4 leads were checked: the directly extracted PMID:31899996 finding verifies the exact variant, case cohort, and 3.0% frequency; other literature leads lacked a verified case-control estimate in the supplied evidence. The ClinGen HBB expert-panel record also reports the variant in 56 individuals with severe beta-thalassemia, but does not provide a control denominator or confidence interval and was not used as the quantitative comparison.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 is met at supporting strength. PMID:6264391 describes the exact HBB intronic G>A variant in a patient doubly heterozygous for beta-thalassemia and Hb Lepore; the variant was identified on the cloned beta-thalassemia allele, while Hb Lepore was the other pathogenic beta-globin allele, supporting occurrence in trans. PMID:31899996 independently reports the exact variant in one compound-heterozygous beta-thalassemia intermedia patient, although that report does not provide explicit parental phase testing. The main PM3 observation therefore supports a recessive genotype with a pathogenic variant in trans, but the phase documentation warrants human review.
For recessive disorders, detected in trans with a pathogenic variant
The variant is intronic (NM_000518.5:c.93-21G>A), so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI reports a maximum delta score of 0.442 (DS_AG), which meets the supplied PP3 supporting threshold of >= 0.2 and does not reach the moderate threshold of >= 0.5. This supports PP3 at supporting strength. The SpliceAI result is used only for PP3 and is not double-counted for BP4 or BP7.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
Expert panel ClinGen Hemoglobinopathy Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
PM2 is not met under the supplied generic supporting threshold of <=0.0001. The default all-comers gnomAD v2.1 grpmax FAF is 0.0002203 and gnomAD v4.1 grpmax FAF is 0.00114218, both above 0.0001. The specified non-cancer subsets do not rescue PM2: gnomAD v2.1 non-cancer exomes have grpmax FAF 0.00021025 and gnomAD v3.1 non-cancer genomes have grpmax FAF 0.00012401, both also above 0.0001. The variant is therefore rare but not rare enough for PM2 under this calibrated generic rule.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BA1 is not met. The required filtering allele frequency is the grpmax FAF, not the highest population point estimate. In the default all-comers datasets, gnomAD v2.1 grpmax FAF is 0.0002203 and gnomAD v4.1 grpmax FAF is 0.00114218, both well below the generic stand-alone threshold of 0.05. The non-cancer subsets also remain below threshold: gnomAD v2.1 non-cancer exomes grpmax FAF 0.00021025 and gnomAD v3.1 non-cancer genomes grpmax FAF 0.00012401. The gnomAD v4.1 highest population point estimate, Middle Eastern AF 0.00197954 from 12/6062 alleles, is not used to override the lower grpmax FAF.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met on the available population data. The filtering allele frequency is the grpmax FAF: 0.0002203 in gnomAD v2.1 all-comers and 0.00114218 in gnomAD v4.1 all-comers, both below the supplied generic default threshold of 0.01. The non-cancer values are likewise below threshold (0.00021025 for gnomAD v2.1 non-cancer exomes and 0.00012401 for gnomAD v3.1 non-cancer genomes). Because the frequency does not approach 1%, no maximum-credible-frequency calculation is needed to reject the default BS1 path; the elevated Middle Eastern popmax point estimate is not the filtering FAF and is based on only 6062 observed alleles.
Allele frequency is greater than expected for the disorder.
BS2 is not met. HBB beta-thalassemia is a recessive disorder, so this criterion would require the variant to be observed in a healthy adult homozygote. gnomAD v2.1 reports 0 homozygotes among 282338 alleles and gnomAD v4.1 reports 0 homozygotes among 1608186 alleles; the non-cancer subsets also report 0 homozygotes. The variant-specific Iranian study instead reports one affected homozygous individual, not a healthy adult homozygote, and therefore does not support BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The variant is intronic, so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI reports a maximum delta score of 0.442, which is above the supplied BP4 supporting threshold of <= 0.1. Therefore, the computational result does not support no impact and BP4 is not met. The SpliceAI result is not reused from PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
The exact-match ClinVar record is Pathogenic with a three-star expert-panel review, not benign or likely benign. No exact-variant ClinVar expert-panel benign classification is present, so the specified BP6 trigger is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific evidence establishes a proband with the disease, absence of family history, and confirmed maternity and paternity for a de novo occurrence of NM_000518.5:c.93-21G>A.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No case-specific assumed-de-novo observation is documented, and there is no evidence describing a proband, parental testing, or whether maternity and paternity were unconfirmed.
Assumed de novo, but without confirmation of paternity and maternity.
PMID:1967205 reports 12 beta-thalassemia heterozygotes from six French-Canadian families and the literature triage identifies the exact variant as segregating in five families, but the accessible record does not provide auditable family-member genotypes, affected-member counts, or meioses sufficient to apply PP1.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The governing rule requires a patient phenotype or family history highly specific for a disease with a single genetic etiology. The supplied case evidence does not provide a patient-specific phenotype or family history for this interpretation, and literature cohort descriptions cannot substitute for the case phenotype.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS3 is not assessed because the available functional evidence does not show that the variant has no damaging effect on protein function or splicing. The older in-vitro transcription experiment reported normal transcription of the cloned beta-globin gene, but it did not measure RNA splicing or protein function; the disease-relevant study instead demonstrated abnormal splicing and reduced HBB production. Therefore, no valid benign functional assay supports BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No family data identify affected relatives who lack NM_000518.5:c.93-21G>A; therefore lack of segregation, and potential phenocopy or multiple-variant explanations, cannot be evaluated.
Lack of segregation in affected members of a family.
BP2 cannot be assessed from the available evidence. The literature reports a compound-heterozygous occurrence and a homozygous occurrence, but does not document the evaluated variant in cis with another pathogenic variant. The reported trans occurrence does not satisfy the BP2 trans path because HBB beta-thalassemia is treated here as a recessive disorder rather than a fully penetrant dominant gene/disorder, and no cis observation is available.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied case and verified literature provide no documented alternate molecular diagnosis for the relevant patient or cohort, so BP5 cannot be adjudicated.
Variant found in a case with an alternate molecular basis for disease.
PVS1 is not applicable under the generic ACMG/AMP definition because NM_000518.5:c.93-21G>A is an intronic c.93-21 variant, not a nonsense, frameshift, canonical +/−1 or 2 splice-site, initiation-codon, or single/multi-exon deletion variant. VariantValidator places it in intron 1 (exon label 1i) and predicts NP_000509.1:p.?; the available functional paper shows aberrant splicing and an intron-retaining transcript, but this does not change the variant into one of the specifically named PVS1 variant types. HBB loss of function is supported as a disease mechanism, but the variant-location/type requirement is not met.
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PS1 is not applicable because the assessed variant is NM_000518.5:c.93-21G>A, an intronic variant with NP_000509.1:p.? rather than an amino-acid change. The rule concerns a same-amino-acid substitution, and its caveat specifically requires caution when changes impact splicing rather than the amino-acid/protein level.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PM1 is not applicable because the variant is intronic and has no assigned amino-acid residue to place in a mutational hotspot or protein functional domain. The HBB domain_tables entry is empty, and the generic rule is directed to a protein-level hotspot or critical functional domain without benign variation.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM4 is not applicable because NM_000518.5:c.93-21G>A is an intronic single-nucleotide substitution with predicted protein consequence NP_000509.1:p.?, not an in-frame deletion, in-frame insertion, or stop-loss variant causing a protein-length change.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
PM5 is not applicable because the assessed variant is intronic with NP_000509.1:p.? and is not a novel missense change at an amino-acid residue. The splicing caveat also excludes treating a non-protein-level intronic change as a same-residue missense comparison.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PP2 is not applicable because its governing definition requires a missense variant, whereas NM_000518.5:c.93-21G>A is intronic and has NP_000509.1:p.? rather than a missense consequence.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
BP1 is not applicable because its governing definition requires a missense variant, whereas NM_000518.5:c.93-21G>A is intronic and has NP_000509.1:p.? rather than a missense consequence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP3 is not applicable because NM_000518.5:c.93-21G>A is an intronic single-nucleotide substitution, not an in-frame deletion or insertion; therefore the repetitive-region and known-function conditions for BP3 cannot apply.
In frame-deletions/insertions in a repetitive region without a known function.
BP7 is limited to synonymous variants. NM_000518.5:c.93-21G>A is an intronic variant (c.93-21), not a synonymous coding variant, so BP7 is outside its governing scope and is not applicable.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Every interpreted variant in HBB, mapped onto the exon structure of NM_000518.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern12 / 6,062 | 0.002 |
| Remaining individuals21 / 62,272 | 0.00034 |
| European (non-Finnish)155 / 1,174,820 | 0.00013 |
| Admixed American6 / 59,988 | 0.0001 |
| Ashkenazi Jewish1 / 29,570 | 3.4e-05 |
| African/African American1 / 74,744 | 1.3e-05 |
| South Asian1 / 90,970 | 1.1e-05 |
| European (non-Finnish)37 / 128,830 | 0.00029 |
| Remaining individuals1 / 7,216 | 0.00014 |
| Admixed American3 / 35,388 | 8.5e-05 |
| South Asian1 / 30,612 | 3.3e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000122498; MAF= 0.01225%, 197/1608186 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00197954; MAF= 0.19795%, 12/6062 alleles, homozygotes = 0); grpmax FAF= 0.00114218.
This variant is present in gnomAD v2.1 (AF= 0.000148758; MAF= 0.01488%, 42/282338 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0002872; MAF= 0.02872%, 37/128830 alleles, homozygotes = 0); grpmax FAF= 0.0002203.
Not available in gnomAD-Canada v1.0.
The variant is intronic (NM_000518.5:c.93-21G>A), so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI reports a maximum delta score of 0.442 (DS_AG), which meets the supplied PP3 supporting threshold of >= 0.2 and does not reach the moderate threshold of >= 0.5. This supports PP3 at supporting strength. The SpliceAI result is used only for PP3 and is not double-counted for BP4 or BP7.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
The variant is intronic, so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable. SpliceAI reports a maximum delta score of 0.442, which is above the supplied BP4 supporting threshold of <= 0.1. Therefore, the computational result does not support no impact and BP4 is not met. The SpliceAI result is not reused from PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
BP7 is limited to synonymous variants. NM_000518.5:c.93-21G>A is an intronic variant (c.93-21), not a synonymous coding variant, so BP7 is outside its governing scope and is not applicable.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.44).
10 paper records listed. 3 cited in the classification.
The severe HBBIVSI-110(G>A) splicing mutation is common in many countries (Supplementary Figure S1),2 results in 90% reduction of HBB (β-globin) and creates aberrant mRNA containing a 19-nt intronic fragment with an in-frame stop codon. Although potent targets of nonsense-mediated decay (NMD), aberrant HBBIVSI-110(G>A) transcripts are abundant in erythroid cells of homozygous patients and disease models,3,4 possibly owing to saturation of NMD by high substrate levels.
Location Main text, page 2, introductory paragraph; functional results in pages 3–6 and Supplementary Discussion, pages 4–5
Context Humanized murine erythroleukemia MEL-HBBIVS cells carrying an HBB IVSI-110(G>A) transgene, plus primary human CD34+ hematopoietic stem/progenitor cells from four HBB IVSI-110(G>A)-homozygous patients. Assays included variant-specific RNA quantification, immunoblotting for HBB protein, erythroid differentiation and hemoglobinization microscopy, and reversed-phase HPLC measurement of HBB/HBA ratios after lentiviral shRNA or GLOBE gene-addition treatment.
The HBB: c.92þ5G>C (bþ) mutation was identified in 6.0% and the HBB: c.93-21G>A (bþ) mutation in 3.0% of the b-TI chromosomes, which suggests that mild b-thal mutations do not represent the major cause in this case.
Location Discussion, paragraph 2; Table 1; Table 2
Context Fifty Iranian patients with beta-thalassemia intermedia from Isfahan were studied. Three prevalent HBB mutations were screened using ARMS-PCR; haplotypes, the XmnI polymorphism, and common alpha-globin deletions were also assessed. The c.93-21G>A variant was present in one compound-heterozygous patient and one homozygous patient.
The first sequence variant lies near the 3* terminus of the small intron. A G residue is replaced by an A residue in the thalassaemic sequence.
Location Results and Discussion, sequence analysis and discussion of the G>A replacement; pp. 1781-1785
Context The HBB gene was cloned and sequenced from a 19-year-old Turkish Cypriot male with severe thalassemia intermedia who was doubly heterozygous for beta-thalassemia and Hb Lepore. The full gene sequence was determined by the Maxam-Gilbert method; no direct functional splicing assay was performed.
beta-Thalassemia minor occurs at approximately 1% frequency in French-Canadians--in families residing in Portneuf County (population approximately 40,000) of Quebec province. We found eight different RFLP haplotypes at the beta-globin gene cluster in 37 normal persons and in 12 beta-thalassemia heterozygotes from six families.
PubMed abstract
Nucleotide sequence analysis of the thalassemic β globin gene revealed only a single nucleotide difference from a normal β globin gene sequence (11) in the internal portion of the small intervening sequence. This G to A transition 22 bases to the 5' side of the 3' junction between the small intervening and coding sequences creates a sequence identical to that at the authentic splice junction at six of seven nucleotides.
Results, “Nucleotide Sequence of the β+-Thalassemic Globin Gene”; Discussion, second paragraph
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000122498; MAF= 0.01225%, 197/1608186 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00197954; MAF= 0.19795%, 12/6062 alleles, homozygotes = 0); grpmax FAF= 0.00114218.
This variant is present in gnomAD v2.1 (AF= 0.000148758; MAF= 0.01488%, 42/282338 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0002872; MAF= 0.02872%, 37/128830 alleles, homozygotes = 0); grpmax FAF= 0.0002203.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (30 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hemoglobinopathy Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 15454)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.44).
This variant has not previously been reported in somatic cancers (COSMIC).