LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-03
Case ID: NM_000518.5_c.93-21G_A_20261103_031533
Framework: ACMG/AMP 2015
Variant classification summary

NM_000518.5:c.93-21G>A

HBB  · NP_000509.1:p.?  · NM_000518.5
GRCh37: chr11:5248050 C>T  ·  GRCh38: chr11:5226820 C>T
Gene: HBB Transcript: NM_000518.5
Final call
Pathogenic
PS3 strong PS4 strong PM3 supporting PP3 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
HBB
Transcript
NM_000518.5
Protein
NP_000509.1:p.?
gnomAD AF
0.00012249826823514196 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong reflects approximately 90% reduced HBB production and an aberrant intron-retaining transcript.
2
Pathogenic: PS4 strong reflects an odds ratio of 15.59 with a 95% confidence interval excluding 1.0.
3
Pathogenic: PM3 supporting reflects occurrence in trans with pathogenic Hb Lepore.
4
Pathogenic: PP3 supporting reflects a SpliceAI maximum delta of 0.442.
5
Pathogenic: PP5 supporting reflects the exact-variant three-star ClinVar expert-panel Pathogenic classification.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; the additional supporting criteria are concordant.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: c.93-21G>A is intronic, outside the ACMG/AMP PVS1 list of nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, or exon-deletion variants.
pvs1_variant_assessment PMID:29700171
PS1 N/A Not applicable: the intronic variant has NP_000509.1:p.? and does not produce an amino-acid change for same-protein-substitution comparison.
cspec
PS2 Not assessed Not assessed: no proband-level de novo observation with both maternity and paternity confirmed is documented.
PS3 Met 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.
PMID:29700171
PS4 Met 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.
PMID:31899996 gnomad_v4 clinvar
PM1 N/A Not applicable: the intronic variant has no assigned amino-acid residue for placement in a protein hotspot or critical functional domain.
cspec
PM2 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00114218, exceeding the supplied PM2 supporting cutoff of 0.0001.
gnomad_v2 gnomad_v4
PM3 Met 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.
PMID:6264391 PMID:31899996
PM4 N/A Not applicable: the intronic single-nucleotide variant has protein consequence p.? and is neither an in-frame indel nor a stop-loss variant.
pvs1_variant_assessment
PM5 N/A Not applicable: the intronic variant has NP_000509.1:p.? and is not a novel missense change at an amino-acid residue.
cspec
PM6 Not assessed Not assessed: no assumed-de-novo case with documented unconfirmed parental relationships is provided.
PP1 Not assessed Not assessed: five reported segregating families lack auditable affected-member genotypes and meiosis counts needed for a segregation determination.
PMID:1967205
PP2 N/A Not applicable: PP2 requires a missense variant, but this intronic variant has NP_000509.1:p.? rather than a missense consequence.
cspec
PP3 Met 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.
spliceai
PP4 Not assessed Not assessed: no patient-specific phenotype or family history is available to determine whether the presentation is highly specific for beta-thalassemia.
PP5 Met Met: the exact variant has a three-star ClinVar Pathogenic classification from the ClinGen Hemoglobinopathy Variant Curation Expert Panel.
clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00114218, below the 0.05 BA1 threshold despite a Middle Eastern point estimate of 0.00197954.
gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00114218, below the generic 0.01 BS1 threshold, so frequency is not greater than expected by the default rule.
gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v4.1 reports 0 homozygotes among 1608186 alleles, while the reported homozygote was affected rather than a healthy adult.
gnomad_v2 gnomad_v4 PMID:31899996
BS3 Not assessed Not assessed: no assay demonstrated absence of damage to splicing or protein function; the available disease-relevant study instead showed abnormal RNA and reduced HBB production.
PMID:29700171 PMID:6264477
BS4 Not assessed Not assessed: no affected relatives without the variant are documented, so lack of segregation cannot be evaluated.
BP1 N/A Not applicable: BP1 requires a missense variant, but this intronic variant has NP_000509.1:p.? rather than a missense consequence.
cspec
BP2 Not assessed Not assessed: no documented cis pathogenic variant is available, and the reported trans observation does not meet the rule's fully penetrant dominant-disorder condition.
PMID:6264391 PMID:31899996
BP3 N/A Not applicable: c.93-21G>A is a single-nucleotide intronic substitution, not an in-frame deletion or insertion in a repetitive region.
pvs1_variant_assessment
BP4 Not met Not met: intronic SpliceAI max delta 0.442 is above the BP4 supporting threshold of <=0.1, indicating predicted splice impact rather than no impact.
spliceai
BP5 Not assessed Not assessed: no documented alternate molecular basis for disease is reported in the available case or verified literature.
BP6 Not met Not met: the exact variant has an expert-panel Pathogenic ClinVar classification, with no expert-panel benign or likely benign classification.
clinvar
BP7 N/A Not applicable: c.93-21G>A is intronic, whereas BP7 applies only to synonymous variants.
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.