rs137853334

Positions:

• chr20-44419813-C-G
• chr20-44419813-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.763C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to glutamate at codon 255 (p.(Gln255Glu)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (ClinVar ID: 437910). In summary, c.763C>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107507/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 6.13

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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	c.763C>G	p.Gln255Glu	missense_variant	7/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.763C>G	p.Gln255Glu	missense_variant	7/10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 30, 2024

The c.763C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to glutamate at codon 255 (p.(Gln255Glu)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (ClinVar ID: 437910). In summary, c.763C>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM2_Supporting. -

Maturity-onset diabetes of the young type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Cologne University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;.;.;T;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;.;N;.;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;.;D;.;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		0.81, 0.94, 0.84, 0.90	.;P;P;.;P;P;.
Vest4		0.61
MutPred		0.52		.;.;.;.;Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);
MVP		0.87
MPC		1.0
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853334; hg19: chr20-43048453;