rs193922480

Positions:

• chr20-44424122-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PM1_Supporting PS4 PP4_Moderate PS2_Moderate PP3

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 NM_175914.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 6.01

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 Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.931C>T	p.Arg311Cys	missense_variant	8/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.931C>T	p.Arg311Cys	missense_variant	8/10	1	NM_175914.5

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

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:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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). -
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	- -

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. -

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. -

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
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
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

Other links and lift over

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