rs193922480

Positions:

chr20-44424122-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM2_SupportingPM1_SupportingPS4PS2_ModeratePP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID:28862987). In summary, c.931C>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, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214003/MONDO:0015967/085

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HNF4A
ENST00000316673.9 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:4U:2

Conservation

PhyloP100: 6.01

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.

PS2

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

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.

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/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.931C>T	p.Arg311Cys	missense_variant	8/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.931C>T	p.Arg311Cys	missense_variant	8/10	1	NM_175914.5	ENSP00000315180		P41235-5

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461164

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 29417725, 28862987, 22060211) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg311 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10768098, 25414397, 26059258, 32533152, 36227502, 36257325). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 36365). This variant is also known as R324C. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 22060211, 28862987, 35089870). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 311 of the HNF4A protein (p.Arg311Cys). -

Maturity onset diabetes mellitus in young

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 08, 2022

Variant summary: HNF4A c.931C>T (p.Arg311Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. This variant is also referred as HNF4A c.997C>T (p.Arg333Cys). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248874 control chromosomes (gnomAD). c.931C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus (examples: Yorifuji_2012, Globa_2017, Johnson_2017, Carlson_2020, and Saint-Martin_2022). Other variants affecting the same amino acid residue (R311H/R311P/R311S) is associated with diabetes/MODY in HGMD. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 28, 2024

The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 28862987). In summary, c.931C>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, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. -

HNF4A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The HNF4A c.931C>T variant is predicted to result in the amino acid substitution p.Arg311Cys. This variant was reported in an individual with diabetes, MODY (Yorifuji et al. 2012. PubMed ID: 22060211; Globa et al. 2017. PubMed ID: 28862987; Mirshahi et al. 2022. PubMed ID: 36257325; McGlacken-Byrne et al. 2022. PubMed ID: 35089870; Marucci et al. 2022. PubMed ID: 36227502; Price et al. 2000. PubMed ID: 10768098; Saint-Martin et al. 2022. PubMed ID: 34556497; Caswell et al. 2020. PubMed ID: 32533152; Carlsson et al. 2019. PubMed ID: 31704690; Delvecchio et al. 2014. PubMed ID: 25414397; Chambers et al. 2015. PubMed ID: 26059258; Johnson et al. 2018. PubMed ID: 29417725). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reviewed by a ClinGen expert panel and is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/36365/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.54

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

33

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

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

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

D

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.71

D

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.1

.;.;.;.;H;H;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.90

D

PROVEAN

Pathogenic

-6.9

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.95

MutPred

0.95

.;.;.;.;Loss of methylation at R333 (P = 0.0148);Loss of methylation at R333 (P = 0.0148);Loss of methylation at R333 (P = 0.0148);

MVP

1.0

MPC

1.2

ClinPred

1.0

D

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.91

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: rs193922480; hg19: chr20-43052762; COSMIC: COSV100290943;