rs762703502

chr12-120994311-CG-Cchr12-120994311-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000545.8(HNF1A):c.864del(p.Pro291GlnfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000961 in 1,457,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G288G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HNF1A
NM_000545.8 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]

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-120994311-CG-C is Pathogenic according to our data. Variant chr12-120994311-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435424.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120994311-CG-C is described in Lovd as [Pathogenic]. Variant chr12-120994311-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.864del	p.Pro291GlnfsTer51	frameshift_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.864del	p.Pro291GlnfsTer51	frameshift_variant	4/10
HNF1A	NM_001406915.1 linkuse as main transcript	c.864del	p.Pro291GlnfsTer51	frameshift_variant	4/9
HNF1A	XM_024449168.2 linkuse as main transcript	c.864del	p.Pro291GlnfsTer51	frameshift_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.864del	p.Pro291GlnfsTer51	frameshift_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152210

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

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0.00

Gnomad AMR

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0.00

Gnomad ASJ

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0.00

Gnomad EAS

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0.00

Gnomad SAS

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0.00

Gnomad FIN

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0.00

Gnomad MID

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0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000961

AC:

AN:

1457192

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

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:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

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0.00

Gnomad4 ASJ

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0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

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0.00

Gnomad4 FIN

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0.00

Gnomad4 NFE

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0.00

Gnomad4 OTH

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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 submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	The 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 submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Frameshift 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 submitter	clinical testing	Invitae	Dec 12, 2023	This 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. -

Maturity onset diabetes mellitus in young

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2018	The 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. -
Likely pathogenic, criteria provided, single submitter	research	Clinical 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. -

Monogenic diabetes

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 30, 2021

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 -

HNF1A-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

The 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 (http://gnomad.broadinstitute.org/variant/12-121432114-CG-C). 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. -

Maturity-onset diabetes of the young type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

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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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over