chr20-44424116-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePP3PM2_SupportingPS4PM1_SupportingPP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.925C>T variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Arginine to Cysteine at codon 309 (p.(Arg309Cys)) of NM_175914.5. This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors). This variant is located within the ligand-binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002970 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant segregated with diabetes, with 1 informative meiosis in each of 3 families with MODY (PP1_moderate; Internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.787, which is greater than to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in several individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, responsiveness to sulfonylureas, and 1 family member with persistent neonatal hypoglycemia) (PP4_Moderate; Internal lab contributors). In summary, c.925C>T meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PM1_Supporting, PM2_Supporting, PP1_Moderate, PP3, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA207744/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8U:4

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS4

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

PM1

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

PM2

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

PP1

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

PP3

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 rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.925C>T	p.Arg309Cys	missense_variant	Exon 8 of 10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.925C>T	p.Arg309Cys	missense_variant	Exon 8 of 10	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248468

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1461144

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 1

Pathogenic:3

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PM1_supporting, PP1_moderate, PP4_moderate, PP3 -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Dec 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young

Pathogenic:2Uncertain:1

Jul 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HNF4A c.925C>T (p.Arg309Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248468 control chromosomes. c.925C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus (e.g. Ellard_2006, Colclough_2013, Colclough_2022, Mirshahi_2022, Yorifuji_2023, Raicevic_2021, Spiro_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 34789499, 23348805, 16917892, 36257325, 33770274, 29998026, 36504295). ClinVar contains an entry for this variant (Variation ID: 36364). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.925C>T (p.R309C) alteration is located in exon 8 (coding exon 8) of the HNF4A gene. This alteration results from a C to T substitution at nucleotide position 925, causing the arginine (R) at amino acid position 309 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/248468) total alleles studied. The highest observed frequency was 0.002% (2/111864) of European (non-Finnish) alleles. This variant was reported in multiple individuals with a diagnosis or suspected diagnosis of MODY (Colclough, 2013; Raicevic, 2021; Mirshahi, 2022; Yorifuji, 2023). Two other alterations at the same codon, c.926G>T (p.R309L) and c.926G>A (p.R309H), have also been detected in individuals with a diagnosis or suspected diagnosis of MODY (Mirshahi, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg331Cys (sometimes called p.Arg322Cys) variant in HNF4A has been reported in 1 individual with Maturity-Onset Diabetes of the Young and 1 individual with prediabetes at age 43 (PMID: 16917892, 29998026), and has been identified in 0.001788% (2/111864) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922479). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 36364). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (Richards 2015). -

not provided

Pathogenic:1Uncertain:2

Aug 30, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the HNF4A protein (p.Arg309Cys). This variant is present in population databases (rs193922479, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 23348805, 29998026, 36208030, 36257325). This variant is also known as c.964C>T (p.Arg322Cys) or c.991C>T (p.Arg331Cys). ClinVar contains an entry for this variant (Variation ID: 36364). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 17, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple unrelated individuals with diabetes or a clinical suspicion for MODY in published literature (PMID: 18356407, 16917892, 29998026, 34789499); however, detailed clinical information was not provided; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R322C), p.(R331C); This variant is associated with the following publications: (PMID: 16917892, 23348805, 34789499, 29998026, 36208030, 36257325, 36504295, 18356407) -

Hyperinsulinemia

Pathogenic:1

Jun 01, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes

Pathogenic:1

Apr 06, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.925C>T variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Arginine to Cysteine at codon 309 (p.(Arg309Cys)) of NM_175914.5. This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors). This variant is located within the ligand-binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002970 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant segregated with diabetes, with 1 informative meiosis in each of 3 families with MODY (PP1_moderate; Internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.787, which is greater than to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in several individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, responsiveness to sulfonylureas, and 1 family member with persistent neonatal hypoglycemia) (PP4_Moderate; Internal lab contributors). In summary, c.925C>T meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PM1_Supporting, PM2_Supporting, PP1_Moderate, PP3, PP4_Moderate. -

HNF4A-related disorder

Uncertain:1

Mar 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HNF4A c.925C>T variant is predicted to result in the amino acid substitution p.Arg309Cys. This variant was reported in multiple individuals with maturity-onset diabetes of the young (MODY) (reported as p.Arg322Cys in Ellard et al. 2006. PubMed ID: 16917892; Colclough. 2013. PubMed ID: 23348805; Mirshahi et al. 2022. PubMed ID: 36257325, supplementary data) and found in an individual with late-onset diabetes and an elevated triglyceride level (documented as c.991C>T, p.Arg331Cy in Spiro et al. 2018. PubMed ID: 29998026). This variant was reported as uncertain in a large population-based cohort study (Table E1, Billings et al. 2022. PubMed ID: 36208030). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;.;T;.;D;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.8

.;.;.;.;M;M;M

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.1

D;.;D;.;D;D;D

REVEL

Pathogenic

0.79

Sift

Benign

0.031

D;.;D;.;D;D;D

Sift4G

Uncertain

0.039

D;T;D;D;D;D;D

Polyphen

0.27, 0.78, 0.86, 0.67

.;B;P;.;P;P;.

Vest4

0.91

MutPred

0.89

.;.;.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);

MVP

1.0

MPC

1.2

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.62

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.

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