rs736823

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_175914.5(HNF4A):c.135C>T(p.Ala45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,613,868 control chromosomes in the GnomAD database, including 2,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 144 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2348 hom. )

Consequence

HNF4A
NM_175914.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.51

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 20-44406143-C-T is Benign according to our data. Variant chr20-44406143-C-T is described in ClinVar as [Benign]. Clinvar id is 129238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44406143-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.135C>T	p.Ala45=	synonymous_variant	2/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.135C>T	p.Ala45=	synonymous_variant	2/10	1	NM_175914.5		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.0356

AC:

5423

AN:

152224

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0342

AC:

8583

AN:

251160

Hom.:

230

AF XY:

0.0333

AC XY:

4524

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00936

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0373

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00477

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0538

Gnomad OTH exome

AF:

0.0363

GnomAD4 exome

AF:

0.0524

AC:

76563

AN:

1461526

Hom.:

2348

Cov.:

AF XY:

0.0507

AC XY:

36855

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00822

Gnomad4 AMR exome

AF:

0.0210

Gnomad4 ASJ exome

AF:

0.0381

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00530

Gnomad4 FIN exome

AF:

0.0427

Gnomad4 NFE exome

AF:

0.0618

Gnomad4 OTH exome

AF:

0.0478

GnomAD4 genome

AF:

0.0356

AC:

5423

AN:

152342

Hom.:

144

Cov.:

AF XY:

0.0337

AC XY:

2511

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0282

Gnomad4 ASJ

AF:

0.0378

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00455

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0569

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0489

Hom.:

287

Bravo

AF:

0.0341

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0529

EpiControl

AF:

0.0485

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial hyperinsulinism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2016

This alteration is classified as 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. -

Maturity-onset diabetes of the young type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Benign

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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