rs762703502

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePVS1

This summary comes from the ClinGen Evidence Repository: The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831842/MONDO:0015967/017

Frequency

Genomes: đť‘“ 0.0 ( 0 hom., cov: 32)
Exomes đť‘“: 0.0000096 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HNF1A
ENST00000257555.11 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 1.68
Variant links:
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 10 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.864del p.Pro291GlnfsTer51 frameshift_variant 4/10 ENST00000257555.11 NP_000536.6
HNF1ANM_001306179.2 linkuse as main transcriptc.864del p.Pro291GlnfsTer51 frameshift_variant 4/10 NP_001293108.2
HNF1ANM_001406915.1 linkuse as main transcriptc.864del p.Pro291GlnfsTer51 frameshift_variant 4/9 NP_001393844.1
HNF1AXM_024449168.2 linkuse as main transcriptc.864del p.Pro291GlnfsTer51 frameshift_variant 4/9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.864del p.Pro291GlnfsTer51 frameshift_variant 4/101 NM_000545.8 ENSP00000257555 P4

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152210
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000961
AC:
14
AN:
1457192
Hom.:
0
Cov.:
33
AF XY:
0.0000152
AC XY:
11
AN XY:
724646
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000228
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.00000811
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:10
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsAug 06, 2020The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 03, 2023Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9313763, 17054605, 30476138, 26287533, 33535453, 34587721, 35112188, 25414397) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 12, 2023This sequence change creates a premature translational stop signal (p.Pro291Glnfs*51) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 26287533). ClinVar contains an entry for this variant (Variation ID: 435424). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 23, 2016- -
Maturity onset diabetes mellitus in young Pathogenic:3
Likely pathogenic, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs762703502 with MODY3. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 15, 2018The c.864delG pathogenic mutation, located in coding exon 4 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 864, causing a translational frameshift with a predicted alternate stop codon (p.P291Qfs*51). This alteration was reported in one individual with diabetes and a family history of early-onset diabetes (Ludovico O et al. PLoS ONE, 2015 Aug;10:e0135855). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 06, 2020The p.Pro291GlnfsX51 variant in HNF1A has been reported in 2 individuals with monogenic diabetes (Delvecchio 2014 PMID: 25414397, Ludovico 2015 PMID: 26287533) and has also been reported in ClinVar (Variation ID: 435424). It has been identified in 0.01% (2/13784) of African chromosomes and 0.01% (8/101808) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 291 and leads to a premature termination codon 51 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant maturity onset diabetes of the young (MODY). In summary although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PS4_Supporting. Please note, this site fails multiple random filters in exomes in gnomAD and is at a multiallelic site; therefore, follow-up Sanger analysis is recommended for exome data. -
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelDec 30, 2021The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate -
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 08, 2016- -
HNF1A-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 04, 2024The HNF1A c.864delG variant is predicted to result in a frameshift and premature protein termination (p.Pro291Glnfs*51). This variant has been reported in individuals with diabetes mellitus or Maturity-Onset Diabetes of the Young (MODY) (e.g., Wheeler et al. 2013. PubMed ID: 24355479; Ludovico et al. 2015. PubMed ID: 26287533; Yalçıntepe et al. 2021. PubMed ID: 33565752). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/435424). Frameshift and other loss-of-function variants in HNF1A are expected to be pathogenic. Based on the collective evidence, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762703502; hg19: chr12-121432114; API