20-44424123-G-T

Variant names:

• chr20-44424123-G-T
• NM_175914.5:c.932G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PP4 PM2_Supporting PM5_Strong PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.932G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to leucine at codon 311 (p.(Arg311Leu)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.932G>A p.Arg311His and c.931C>T p.Arg311Cys, have been interpreted as pathogenic by the ClinGen MDEP and p.Arg311Leu has a greater Grantham distance than p.Arg311His (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.932G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409108272/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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	c.932G>T	p.Arg311Leu	missense_variant	Exon 8 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.932G>T	p.Arg311Leu	missense_variant	Exon 8 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Jul 31, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.932G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to leucine at codon 311 (p.(Arg311Leu)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.932G>A p.Arg311His and c.931C>T p.Arg311Cys, have been interpreted as pathogenic by the ClinGen MDEP and p.Arg311Leu has a greater Grantham distance than p.Arg311His (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.932G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM1_Supporting, PM2_Supporting. -

not specified Uncertain:1

Jul 23, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the HNF4A gene demonstrated a sequence change, c.932G>T, in exon 8 that results in an amino acid change, p.Arg311Leu. This sequence change does not appear to have been previously described in individuals with HNF4A-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Arg311Leu change affects a highly conserved amino acid residue located in a domain of the HNF4A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg311Leu substitution. Other amino acid substitutions at this position (p.Arg311His, p.Arg311Cys) have been reported in individuals with maturity-onset diabetes of the young (PMID: 24947580, 22060211, 26059258). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg311Leu change remains unknown at this time. Heterozygous pathogenic variants in HNF4A are associated with Fanconi renotubular syndrome4, with maturity-onset diabetes of the young [OMIM# 616026] -

not provided Uncertain:1

Mar 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 2018786). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 311 of the HNF4A protein (p.Arg311Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNF4A-related conditions. 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. 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: 25414397, 36257325). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;.;T;.;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;.;H;H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.1	D;.;D;.;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.
Vest4		0.96
MutPred		0.93		.;.;.;.;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		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43052763;