rs145902391

Positions:

chr20-44424035-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. 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 (PMID:27913849). In summary, c.844G>A 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): no criteria met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870393/MONDO:0015967/085

Frequency

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

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:5

Conservation

PhyloP100: 10.0

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.844G>A	p.Asp282Asn	missense_variant	8/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.844G>A	p.Asp282Asn	missense_variant	8/10	1	NM_175914.5	ENSP00000315180		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

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:

0.0000121

AC:

AN:

247032

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460818

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Sep 26, 2024	The c.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. 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 (PMID: 27913849). In summary, c.844G>A 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): no criteria met. -
Uncertain significance, criteria provided, single submitter	research	Personalized Diabetes Medicine Program, University of Maryland School of Medicine	Feb 03, 2016	ACMG Criteria: PP3, BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 21, 2017

- -

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

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2020

The p.D282N variant (also known as c.844G>A), located in coding exon 8 of the HNF4A gene, results from a G to A substitution at nucleotide position 844. The aspartic acid at codon 282 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in one antibody positive individual in the Norwegian Childhood Diabetes Registry (Johansson BB et al. Diabetologia, 2017 04;60:625-635). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.34

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

Eigen

Benign

0.013

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.60

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

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.98

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.42

Sift

Benign

0.59

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

Sift4G

Benign

0.47

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

Polyphen

0.0010, 0.041, 0.015, 0.056

.;B;B;.;B;B;.

Vest4

0.76

MVP

0.81

MPC

0.86

ClinPred

0.65

GERP RS

5.4

Varity_R

0.44

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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