rs193922479

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM1_SupportingPM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.925C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to serine at codon 309 (p.(Arg309Ser)) of NM_175914.5. 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 0.737, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.c.925C>T, p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309Ser (PM5_Supporting). In summary, c.778G>T 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): PM2_supporting, PP3, PM1_supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409108243/MONDO:0015967/085

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.925C>A	p.Arg309Ser	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>A	p.Arg309Ser	missense_variant	Exon 8 of 10	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461144

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726858

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Sep 26, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.925C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to serine at codon 309 (p.(Arg309Ser)) of NM_175914.5. 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 0.737, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.c.925C>T, p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309Ser (PM5_Supporting). In summary, c.778G>T 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): PM2_supporting, PP3, PM1_supporting, PM5_supporting. -

not provided

Uncertain:1

May 02, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

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

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.6

.;.;.;.;L;L;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.74

Sift

Benign

0.098

T;.;T;.;T;T;T

Sift4G

Benign

0.21

T;T;T;T;T;T;T

Polyphen

0.051, 0.89, 0.94, 0.47

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

Vest4

0.87

MutPred

0.55

.;.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.99

MPC

1.0

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.65

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