20-44424116-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_175914.5(HNF4A):c.925C>T(p.Arg309Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R309L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5U:4

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_175914.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-44424117-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 972810.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 20-44424116-C-T is Pathogenic according to our data. Variant chr20-44424116-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36364.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44424116-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.925C>T	p.Arg309Cys	missense_variant	8/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.925C>T	p.Arg309Cys	missense_variant	8/10	1	NM_175914.5		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248468

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1461144

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PS4, PM1_supporting, PP1_moderate, PP4_moderate, PP3 -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the HNF4A protein (p.Arg309Cys). This variant is present in population databases (rs193922479, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 23348805, 29998026, 36208030, 36257325). This variant is also known as c.964C>T (p.Arg322Cys) or c.991C>T (p.Arg331Cys). ClinVar contains an entry for this variant (Variation ID: 36364). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	Reported in unrelated individuals with diabetes in published literature (Ellard et al., 2006; Harries et al., 2008; Spiro et al., 2018; Colclough et al., 2021); detailed clinical information was not provided on these individuals and alternative nomenclature (p.(R322C) and p.(R331C)) was utilized in some publications; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16917892, 23348805, 34789499, 29998026, 36208030, 36257325, 36504295, 18356407) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -

Hyperinsulinemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2015

- -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 06, 2024

The c.925C>T variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Arginine to Cysteine at codon 309 (p.(Arg309Cys)) of NM_175914.5. This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors). This variant is located within the ligand-binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002970 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant segregated with diabetes, with 1 informative meiosis in each of 3 families with MODY (PP1_moderate; Internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.787, which is greater than to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in several individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, responsiveness to sulfonylureas, and 1 family member with persistent neonatal hypoglycemia) (PP4_Moderate; Internal lab contributors). In summary, c.925C>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, PM1_Supporting, PM2_Supporting, PP1_Moderate, PP3, PP4_Moderate. -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg331Cys (sometimes called p.Arg322Cys) variant in HNF4A has been reported in 1 individual with Maturity-Onset Diabetes of the Young and 1 individual with prediabetes at age 43 (PMID: 16917892, 29998026), and has been identified in 0.001788% (2/111864) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922479). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 36364). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.94

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.1

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

REVEL

Pathogenic

0.79

Sift

Benign

0.031

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

Sift4G

Uncertain

0.039

D;T;D;D;D;D;D

Polyphen

0.27, 0.78, 0.86, 0.67

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

Vest4

0.91

MutPred

0.89

.;.;.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);

MVP

1.0

MPC

1.2

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.62

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