The HNF1A NM_000545.8:c.872dup (NP_000536.6:p.(Gly292ArgfsTer25)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV57458765, n = 65 times). Based on available guidelines, this variant is considered to be Benign. This variant is considered to be Pathogenic by the VCEP (ClinGen Monogenic Diabetes Variant Curation Expert Panel; ClinVar ID 14927).
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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.HNF1A encodes a transcription factor that helps control the activity of genes important for liver function and pancreatic islet cells. Inherited loss of HNF1A function causes maturity-onset diabetes of the young type 3 (MODY3), and changes in the gene can lead to hepatic adenomas. HNF1A acts as a tumor suppressor, with its inactivation commonly associated with hepatocellular adenomas and rarely found in hepatocellular carcinoma.
The recorded framework is ClinGen HNF1A VCEP v3.1. 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, very strong: exon 4 frameshift c.872dup lies 5' of c.1714, and the exact P291fsinsC transcript was reduced to 6% of normal by NMD.
Not applicable: the HNF1A VCEP explicitly prohibits use of PP5 for this VCEP.
Met: gnomAD v2.1 grpmax FAF 0.00038181 exceeds the VCEP BA1 threshold of 0.0001, although gnomAD v4.1 reports 0.00002301.
Met: gnomAD v2.1 grpmax FAF 0.00038181 exceeds the VCEP BS1 threshold of 0.000033, while gnomAD v4.1 reports 0.00002301.
Benign: BA1 (stand-alone benign) satisfies the HNF1A Expert Panel's Rule 17; BS1 is additionally met, while PVS1 alone does not satisfy a pathogenic rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 84 / 1,604,382 alleles. Recorded AF 5.23566e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000331629; MAF= 0.03316%, 86/259326 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000484966; MAF= 0.04850%, 9/18558 alleles, homozygotes = 0); grpmax FAF= 0.00038181.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.014. Refer to the recorded PP3/BP4 rationale for interpretation.
13 Pathogenic · 1 pathogenic. ClinVar API review status: reviewed by expert panel.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV57458765, n = 65 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen HNF1A VCEP v3.1, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 3 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength because the exact variant is a frameshift in exon 4, within the VCEP's exons 1-9 5' of c.1768 path and 5' of the c.1714 NMD boundary.
PM4 is not applicable because the VCEP PM4 specification addresses in-frame amino-acid deletions or insertions, not this one-nucleotide frameshift.
BP3 is not applicable because the HNF1A VCEP explicitly marks BP3 Not Applicable.
Among the requested codon/residue/domain criteria, PS1, PM5, PP2, and BP1 are not applicable under the HNF1A VCEP specification; PM1 is not met because codon 292 is outside the specified approved regions and the VCEP does not define a hotspot route.
The recurrent c.872dup/P291fsinsC reports in PMID:12574234 and PMID:12355088 were reviewed for possible hotspot evidence but cannot override the VCEP's restricted PM1 rule.
PS4 is not met because the VCEP's mandatory PM2_Supporting prerequisite fails despite nine unrelated occurrences meeting the occurrence-count threshold.
PP4 is not assessed because the required patient-specific MPC and HNF4A results are unavailable.
PP5 and BP6 are not applicable under the HNF1A VCEP; BP5 is not assessed because no alternate P/LP monogenic-diabetes variant is documented.
All three requested computational criteria are not_applicable because NM_000545.8:c.872dup is a coding frameshift, outside the applicable non-canonical/synonymous or non-protein-altering computational paths in the HNF1A VCEP rules.
The available SpliceAI max delta score of 0.014 is not double-counted or applied outside the governing criterion scope.
No criteria match.
NM_000545.8:c.872dup is a frameshift in exon 4 of HNF1A, producing NP_000536.6:p.(Gly292ArgfsTer25), well 5' of c.1768 and 5' of the c.1714 NMD boundary. The governing HNF1A PVS1 decision tree assigns very strong PVS1 to frameshift variants in exons 1-9 5' of c.1768, with NMD expected 5' of c.1714. The exact variant is also reported as P291fsinsC in a lymphoblastoid-cell study: mutant transcript abundance was 6% of normal and increased 81-fold after cycloheximide, supporting NMD. The searched VCEP decision-tree file contained no variant-specific row for c.872dup, p.Gly292ArgfsTer25, or p.G292Rfs*25; the governing frameshift/exon rule therefore controls.
Frameshift | Exons 1-9 (5' of c.1768). NMD is expected for variants 5' of c.1714. While NMD is not expected to occur for variants in the last 55 base pairs of exon 9 (c.1714 - c.1768), this region is known to be enriched for MODY-causing nonsense. | PVS1
Expert panel ClinGen Monogenic Diabetes Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1 is met under the HNF1A VCEP rule because the default all-comers gnomAD v2.1 record has grpmax FAF 0.00038181 (0.038181%), exceeding the VCEP threshold of 0.0001 (0.01%). gnomAD v4.1 reports a lower grpmax FAF of 0.00002301 (0.002301%), below the BA1 threshold, creating a version-dependent population-frequency discrepancy that warrants human review; the VCEP does not specify substituting the non-cancer subsets.
gnomAD Grpmax FAF ≥ 1:10,000 (≥ 0.01% or 0.0001)
BS1 is met under the HNF1A VCEP rule because the default all-comers gnomAD v2.1 record has grpmax FAF 0.00038181 (0.038181%), exceeding the VCEP threshold of 0.000033 (0.0033%). gnomAD v4.1 reports grpmax FAF 0.00002301 (0.002301%), below that threshold, so the result is version-dependent and requires human review; the VCEP does not specify use of the non-cancer subsets.
gnomAD Grpmax FAF ≥ 1:30,000 (≥0.0033% or 0.000033)
The VCEP requires PM2_Supporting before PS4 can be used at any level. PMID:12574234 directly identifies the same c.872dup frameshift as P291fsinsC in nine Norwegian MODY3 families, which meets the VCEP's seven-or-more-unrelated-occurrences Strong rule. However, gnomAD v4.1 reports grpmax FAF 0.00002301, while the VCEP PM2_Supporting rule is gnomAD Grpmax FAF <= 0.000003; explicit comparison: 0.00002301 <= 0.000003? no. Therefore PS4 cannot be applied. The literature packet's ai_classified_papers contains no paper classified as PS4; the relevant occurrence report was verified in its full-text extraction.
Variant should meet PM2\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). ... Seven or more unrelated occurrences = Strong.
The variant affects codon 292. It is outside the VCEP-defined dimerization region (codons 1-32) and DNA-binding subsets (codons 107-174 and 201-280), and it is not one of the specifically listed DNA-contact residues (the highest listed residue is Lys273). The VCEP PM1 specification does not provide a somatic-hotspot route, so recurrence of the same frameshift in PMID:12574234 and PMID:12355088 cannot establish PM1 under this governing rule.
Use for defined regions in the DNA binding and dimerization domains. ... * Dimerization: codons 1-32, NM\_000545.8 ... * Subset of DNA binding domains: codons 107-174 and 201-280
PM2 is not met because the VCEP requires gnomAD Grpmax FAF <= 0.000003, while the default all-comers gnomAD v2.1 and v4.1 records report grpmax FAF values of 0.00038181 and 0.00002301, respectively; both exceed the threshold. The VCEP does not specify replacing these with non-cancer subsets.
gnomAD Grpmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%)
The HNF1A VCEP directs PS2 to the point-based system with phenotype consistency specifications. The case evidence does not document a proband with confirmed de novo status, parental testing, confirmed parental relationships, phenotype-specific point assignment, or a pre-assigned PS2 code. The governing PS2_DeNovo_Points_Table.pdf was searched for c.872dup, p.Gly292ArgfsTer25, and p.G292Rfs*25, with no variant-specific entry found; therefore a PS2 point total and strength cannot be determined.
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
The variant-specific study of P291fsinsC/c.872dup used allele-specific quantitative RT-PCR in patient-derived lymphoblastoid cell lines and found mutant transcript abundance of 6% of the normal allele, restored by cycloheximide, consistent with nonsense-mediated decay. However, the HNF1A VCEP PS3 specification limits supporting PS3 to approved luciferase transactivation, EMSA DNA-binding, or western blotting/immunofluorescence studies, and limits moderate PS3 to the specified Gloyn/Oxford luciferase assay; this RNA NMD assay does not satisfy one of those listed PS3 paths. The variant is a coding frameshift, not a non-canonical splice-site variant eligible for the VCEP strong PS3 rule.
PS3 should be applied at the supporting level for the following approved functional studies and cutoffs except as noted in the PS3\_Moderate specification: 1. Luciferase assays for transactivation: less than 40% activity of wildtype (WT). Assays should include controls for WT, T2DM-risk, and known MODY variants. 2. EMSA for DNA binding: less than 40% activity of WT. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) [<sup>4</sup>](#pmid_11162430), [<sup>5</sup>](#pmid_12574234), [<sup>6</sup>](#pmid_24915262). 3. Western blotting and indirect immunofluorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589\_615del (p.Lys197\_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).
The VCEP applies Jarvik and Browning meiosis thresholds: in a single family, 3, 4, or 5 meioses correspond to Supporting, Moderate, or Strong at probabilities of 1/8, 1/16, or 1/32 or lower; thresholds are less stringent for more than one family. PMID:12574234 reports the exact-equivalent P291fsinsC variant in nine Norwegian MODY3 families comprising 31 individuals, but the extracted report does not provide variant-positive and variant-negative relatives, informative meioses, or a calculated cosegregation probability. The reported family count and affected-individual count cannot be converted to PP1 strength under the VCEP rule.
Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918) * Single Family : ≤ 1/32 (5 meioses) * \>1 Family : ≤ 1/16 (4 meioses)...Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918) * Single Family : ≤ 1/16 (4 meioses) * \>1 Family : ≤ 1/8 (3 meioses)...Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918) * Single Family : ≤ 1/8 (3 meioses) * \>1 Family : ≤ ¼ (2 meioses)
The VCEP requires an MPC result >=50% and negative HNF4A testing for PP4 Supporting; PP4 Moderate additionally requires at least one specified HNF1A-MODY feature. The available evidence does not provide this patient's MPC result, HNF4A test result, or sufficient patient-specific qualifying phenotype data, so PP4 cannot be evaluated under the VCEP rule.
MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing
BS2 cannot be assessed because the VCEP requires genotype-positive, phenotype-negative normoglycemic individuals age 70 or older, and the available population data provide allele counts and homozygote counts but no qualifying individuals' age or glycemic phenotype.
Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)
No VCEP-qualifying benign functional result is available. The variant is a coding frameshift rather than a non-canonical splice-site variant with RNA and in silico evidence of normal splicing. The available variant-specific RNA study instead showed marked transcript depletion to 6% of normal, and no approved luciferase or EMSA result at or above the VCEP's 75% wild-type threshold is reported. The VCEP also requires BS3 functional studies to be performed on a transfected variant; the available study used patient-derived lymphoblastoid cell lines.
To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. BS3 should be applied at the supporting level for the following approved functional studies and cutoffs: 1. Luciferase assays for transactivation: \u2265 75% activity of wildtype 2. EMSA for DNA binding: \u2265 75% activity of wildtype. 3. Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.
The VCEP limits BS4 to family members without the variant who have MPC score >50%, meaning genotype-negative, phenotype-positive relatives. The available case evidence contains no identified family member with a documented negative genotype, positive phenotype, and MPC score >50%; therefore BS4 cannot be assessed.
Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).
The HNF1A VCEP permits BP2 at Supporting strength when the variant is in cis or trans with a likely pathogenic variant. The available case evidence does not document a second likely pathogenic variant or establish cis/trans phase for NM_000545.8:c.872dup, so BP2 cannot be evaluated.
Also applicable when in cis or trans with a likely pathogenic variant.
The VCEP BP5 rule requires a variant in another monogenic diabetes gene to be classified P/LP. No qualifying alternate-gene variant or P/LP classification is documented in the available case evidence, so BP5 cannot be evaluated.
A variant in other monogenic diabetes gene is P/LP.
PS1 is not applicable because the observed variant is a frameshift, NP_000536.6:p.(Gly292ArgfsTer25), rather than a same-amino-acid change. The VCEP's splice-based PS1 route is also not applicable because the available variant consequence is a coding frameshift and no qualifying comparison of SpliceAI scores to a pathogenic or likely pathogenic splice variant is established.
Applicable for a same amino acid change if the previously established variant is classified as pathogenic by ClinGen MDEP specifications.
PM3 is not applicable under the ClinGen Monogenic Diabetes Expert Panel HNF1A Version 3.1 specification. No PM3 evidence assessment is therefore permitted under this governing framework.
Not Applicable
The VCEP PM4 specification applies to deletions or insertions of more than one amino acid in a non-repeat region, or to single-amino-acid deletions or insertions. This variant is a frameshift insertion of one nucleotide that creates a premature termination codon, not an in-frame amino-acid deletion or insertion; PM4 is therefore outside the VCEP-defined applicability. The searched HNF1A_PVS1_Decision_Tree_20230625.pdf.txt contained no variant-specific entry for the requested notations.
For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence. ... For single amino acid deletions/insertions, use as supporting level of evidence
PM5 is not applicable because the observed variant is a frameshift, not a novel amino acid change to be compared with a different pathogenic or likely pathogenic amino acid change at the same residue.
The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.
The HNF1A VCEP CSPEC explicitly marks PM6 as Not Applicable. The governing PS2_DeNovo_Points_Table.pdf was searched for c.872dup, p.Gly292ArgfsTer25, and p.G292Rfs*25, with no variant-specific pre-assigned PM6 entry found; no PM6 evidence can be applied under this VCEP specification.
Not Applicable
PP2 is explicitly not applicable in the ClinGen MDEP HNF1A v3.1 specification because the gene-level constraint score is not significant and the VCEP does not support use of this criterion at this time.
Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time.
The HNF1A VCEP rule provides a REVEL path for predicted protein impact and a SpliceAI path specifically for non-canonical splicing and synonymous variants. NM_000545.8:c.872dup is a coding frameshift, not a synonymous or non-canonical splice-site variant; therefore PP3 is outside the governing rule's applicable scope. The available SpliceAI max delta score of 0.014 is not used to convert this frameshift into PP3.
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2[<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
BP1 is explicitly not applicable in the ClinGen MDEP HNF1A v3.1 specification.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The HNF1A VCEP specification explicitly marks BP3 as Not Applicable. No BP3 evidence is therefore assessed, regardless of the variant's location in the exon 4 poly-C tract. The searched HNF1A_PVS1_Decision_Tree_20230625.pdf.txt contained no variant-specific entry for c.872dup, p.Gly292ArgfsTer25, or p.G292Rfs*25.
Not Applicable
The HNF1A VCEP permits SpliceAI BP4 for non-canonical splicing and synonymous variants, and its REVEL path concerns predicted lack of protein impact. NM_000545.8:c.872dup is a coding frameshift. Under the governing scope, BP4 is not applicable: a low SpliceAI score cannot negate the truncating protein consequence.
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 [<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
The HNF1A VCEP marks BP6 not applicable for this VCEP and states that the criterion is not for use.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7 is the benign computational rule for a non-protein-altering sequence change evaluated by SpliceAI and phyloP100. NM_000545.8:c.872dup is a coding frameshift with a predicted truncated protein, not a synonymous/non-protein-altering variant; therefore BP7 is outside its applicable scope. The SpliceAI max delta score of 0.014 is not independently used for BP7.
Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \< 2.0.
Every interpreted variant in HNF1A, mapped onto the exon structure of NM_000545.8. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)55 / 62,926 | 0.00087 |
| Admixed American4 / 58,294 | 6.9e-05 |
| South Asian3 / 90,328 | 3.3e-05 |
| Remaining individuals2 / 62,094 | 3.2e-05 |
| East Asian1 / 44,764 | 2.2e-05 |
| European (non-Finnish)18 / 1,175,090 | 1.5e-05 |
| African/African American1 / 74,602 | 1.3e-05 |
| East Asian9 / 18,558 | 0.00048 |
| European (non-Finnish)50 / 117,130 | 0.00043 |
| Ashkenazi Jewish4 / 9,782 | 0.00041 |
| African/African American8 / 22,394 | 0.00036 |
| Remaining individuals2 / 6,716 | 0.0003 |
| Admixed American7 / 32,938 | 0.00021 |
| South Asian4 / 28,834 | 0.00014 |
| European (Finnish)2 / 22,974 | 8.7e-05 |
This variant is present in gnomAD v4.1 (AF= 5.23566e-05; MAF= 0.00524%, 84/1604382 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000874043; MAF= 0.08740%, 55/62926 alleles, homozygotes = 0); grpmax FAF= 2.301e-05.
This variant is present in gnomAD v2.1 (AF= 0.000331629; MAF= 0.03316%, 86/259326 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000484966; MAF= 0.04850%, 9/18558 alleles, homozygotes = 0); grpmax FAF= 0.00038181.
Not available in gnomAD-Canada v1.0.
The HNF1A VCEP rule provides a REVEL path for predicted protein impact and a SpliceAI path specifically for non-canonical splicing and synonymous variants. NM_000545.8:c.872dup is a coding frameshift, not a synonymous or non-canonical splice-site variant; therefore PP3 is outside the governing rule's applicable scope. The available SpliceAI max delta score of 0.014 is not used to convert this frameshift into PP3.
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2[<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
The HNF1A VCEP permits SpliceAI BP4 for non-canonical splicing and synonymous variants, and its REVEL path concerns predicted lack of protein impact. NM_000545.8:c.872dup is a coding frameshift. Under the governing scope, BP4 is not applicable: a low SpliceAI score cannot negate the truncating protein consequence.
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 [<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
BP7 is the benign computational rule for a non-protein-altering sequence change evaluated by SpliceAI and phyloP100. NM_000545.8:c.872dup is a coding frameshift with a predicted truncated protein, not a synonymous/non-protein-altering variant; therefore BP7 is outside its applicable scope. The SpliceAI max delta score of 0.014 is not independently used for BP7.
Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \< 2.0.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
6 paper records listed. 1 cited in the classification.
These results indicate that the observed reduction in mutant allele frequency is due to NMD.
Location Results, paragraph beginning 'We quantified the levels of mutant mRNA'; page 501; Table 1; Table 2
Context Allele-specific quantitative RT-PCR in Epstein-Barr-virus-transformed lymphoblastoid cell lines from heterozygous HNF1A mutation carriers; cycloheximide inhibition of translation was used to test whether reduced mutant transcript abundance reflected NMD.
The previously described frameshift mutation P291fsinsC in exon 4 (16, 19) was the most prevalent Norwegian MODY3 mutation and was identified in nine families (Table 1).
Results, "Screening HNF-1α for mutations and normal variants"; Table 1
This frameshift mutation, which leads to protein truncation (Pro291fsX316), has been observed previously in 20% of individuals with MODY3
Results, paragraph beginning "Using sequence analysis"; Table 1; Fig. 2
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
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= 5.23566e-05; MAF= 0.00524%, 84/1604382 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000874043; MAF= 0.08740%, 55/62926 alleles, homozygotes = 0); grpmax FAF= 2.301e-05.
This variant is present in gnomAD v2.1 (AF= 0.000331629; MAF= 0.03316%, 86/259326 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000484966; MAF= 0.04850%, 9/18558 alleles, homozygotes = 0); grpmax FAF= 0.00038181.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Monogenic Diabetes Variant Curation Expert Panel (expert panel). (ClinVarID = 14927)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57458765, n = 65 times).
This variant does not lie in a statistically significant hotspot.