rs374298096

Positions:

chr20-44413782-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP7

This summary comes from the ClinGen Evidence Repository: The c.408G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 136 (p.(Ala136=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.087, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.408G>A variant in gnomAD v2.1.1 is 0.00002619, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.408G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870243/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:6

Conservation

PhyloP100: -1.10

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:

HNF4A (HGNC:):

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

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.408G>A	p.Ala136Ala	synonymous_variant	4/10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.408G>A	p.Ala136Ala	synonymous_variant	4/10	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000136

AC:

AN:

249214

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

134812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00279

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000989

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1460596

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726594

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000289

Hom.:

Bravo

AF:

0.000106

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2023	- -

Maturity onset diabetes mellitus in young

Benign:2

Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs374298096 in MODY, yet. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Monogenic diabetes

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 12, 2023

The c.408G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 136 (p.(Ala136=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.087, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.408G>A variant in gnomAD v2.1.1 is 0.00002619, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.408G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.7

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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