rs745975

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175914.5(HNF4A):c.50-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,609,480 control chromosomes in the GnomAD database, including 40,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2830 hom., cov: 33)

Exomes 𝑓: 0.22 ( 38050 hom. )

Consequence

HNF4A
NM_175914.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001241

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.18

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 20-44406053-C-T is Benign according to our data. Variant chr20-44406053-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44406053-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 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.50-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.50-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_175914.5		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27706

AN:

152172

Hom.:

2828

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.197

AC:

49450

AN:

250434

Hom.:

5418

AF XY:

0.205

AC XY:

27829

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.0978

Gnomad AMR exome

AF:

0.0978

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.174

Gnomad SAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.226

Gnomad OTH exome

AF:

0.217

GnomAD4 exome

AF:

0.224

AC:

326643

AN:

1457190

Hom.:

38050

Cov.:

AF XY:

0.225

AC XY:

163452

AN XY:

725146

show subpopulations

Gnomad4 AFR exome

AF:

0.0951

Gnomad4 AMR exome

AF:

0.103

Gnomad4 ASJ exome

AF:

0.310

Gnomad4 EAS exome

AF:

0.181

Gnomad4 SAS exome

AF:

0.238

Gnomad4 FIN exome

AF:

0.194

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.226

GnomAD4 genome

AF:

0.182

AC:

27724

AN:

152290

Hom.:

2830

Cov.:

AF XY:

0.180

AC XY:

13384

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.140

Gnomad4 ASJ

AF:

0.315

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.215

Gnomad4 FIN

AF:

0.178

Gnomad4 NFE

AF:

0.230

Gnomad4 OTH

AF:

0.195

Alfa

AF:

0.217

Hom.:

4732

Bravo

AF:

0.177

Asia WGS

AF:

0.201

AC:

700

AN:

3478

EpiCase

AF:

0.222

EpiControl

AF:

0.224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2019	The c.95-5C>T variant in HNF4A is classified as benign because it has been identified in 19.56% (55114/281792) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org/). Additionally, this variant does not alter the splice consensus sequence and is not predicted to impact splicing. ACMG/AMP criteria applied: BA1, BP4. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 10983627, 25266181) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Maturity onset diabetes mellitus in young

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Glycosuria

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. As rs745975 SNP of HNF4α gene is associated with whole body insulin sensitivity and glucose tolerance and these factors are modulated by physical activity. -

Hyperinsulinism, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

Cadd

Benign

0.24

Dann

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

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