rs142204928

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_175914.5(HNF4A):c.439G>A(p.Val147Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,614,194 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 20 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11O:1

Conservation

PhyloP100: 1.24

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
hyperinsulinism due to HNF4A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075802803).

BP6

Variant 20-44414519-G-A is Benign according to our data. Variant chr20-44414519-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36353.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000722 (110/152334) while in subpopulation SAS AF = 0.0141 (68/4830). AF 95% confidence interval is 0.0114. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.439G>A	p.Val147Ile	missense_variant	Exon 5 of 10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.439G>A	p.Val147Ile	missense_variant	Exon 5 of 10	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00288

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00201

AC:

505

AN:

251390

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000984

AC:

1438

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

968

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00174

AC:

AN:

39700

South Asian (SAS)

AF:

0.0123

AC:

1065

AN:

86238

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000186

AC:

207

AN:

1112008

Other (OTH)

AF:

0.00141

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152334

Hom.:

Cov.:

AF XY:

0.000832

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00289

AC:

AN:

5188

South Asian (SAS)

AF:

0.0141

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000399

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 13, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32621647, 31216263, 25041077, 27080136, 27535533, 27810688, 15281001, 24097065) -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNF4A: BP4, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

May 02, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Type 2 diabetes mellitus

Uncertain:1Benign:1

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 individuals without diabetes mellitus (PMID: 15281001, 24097065), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Maturity-onset diabetes of the young type 1

Benign:1Other:1

Oct 02, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hyperinsulinism

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Maturity onset diabetes mellitus in young

Benign:1

Apr 27, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.23

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.79

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

MetaRNN

Benign

0.0076

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

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.90

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

PhyloP100

1.2

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.23

N;.;N;.;N;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.49

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

Sift4G

Benign

0.30

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

Polyphen

0.0010, 0.0

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

Vest4

0.15

MVP

0.97

MPC

0.23

ClinPred

0.0069

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.074

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over