20-44355811-A-C

Position:

chr20-44355811-A-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP5

This summary comes from the ClinGen Evidence Repository: The c.7A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to arginine at codon 3 (p.(Ser3Arg)) of NM_175914.5. This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. While c.7A>C has a GrpMax filtering allele frequency of less than 0.000003 in the European non-Finnish population in gnomAD v2.1.1, but it has 11 copies in the Ashkenazi Jewish subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.7A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870022/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:1

Conservation

PhyloP100: 5.47

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 -1 ACMG points.

BP5

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 linkuse as main transcript	c.7A>C	p.Ser3Arg	missense_variant	1/10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.7A>C	p.Ser3Arg	missense_variant	1/10	1	NM_175914.5	ENSP00000315180.4	P41235-5
HNF4A	ENST00000457232.5 linkuse as main transcript	c.7A>C	p.Ser3Arg	missense_variant	1/10	1		ENSP00000396216.1	P41235-6
HNF4A	ENST00000609795.5 linkuse as main transcript	c.7A>C	p.Ser3Arg	missense_variant	1/8	1		ENSP00000476609.1	P41235-7
HNF4A	ENST00000609262 linkuse as main transcript	c.-225A>C		5_prime_UTR_variant	1/4	1		ENSP00000476310.1	B9VVT8

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000606

AC:

AN:

247386

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00110

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:

0.000333

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 23, 2022

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2019

The p.S3R variant (also known as c.7A>C), located in coding exon 1 of the HNF4A gene, results from an A to C substitution at nucleotide position 7. The serine at codon 3 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Monogenic diabetes

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 03, 2025

The c.7A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to arginine at codon 3 (p.(Ser3Arg)) of NM_175914.5. This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. While c.7A>C has a GrpMax filtering allele frequency of less than 0.000003 in the European non-Finnish population in gnomAD v2.1.1, but it has 11 copies in the Ashkenazi Jewish subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.7A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP5. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

0.013

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.50

T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Uncertain

0.13

PROVEAN

Benign

-0.80

N;.;N

REVEL

Benign

0.26

Sift

Uncertain

0.0030

D;.;D

Sift4G

Benign

0.34

T;T;T

Polyphen

0.40, 0.19

.;B;B

Vest4

0.36

MutPred

0.35

Gain of methylation at S3 (P = 0.0074);Gain of methylation at S3 (P = 0.0074);Gain of methylation at S3 (P = 0.0074);

MVP

0.77

ClinPred

0.15

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

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