rs1800961

Positions:

chr20-44413724-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_175914.5(HNF4A):c.350C>T(p.Thr117Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,536 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 74 hom., cov: 31)

Exomes 𝑓: 0.030 ( 748 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.87

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 -18 ACMG points.

PM1

In a zinc_finger_region NR C4-type (size 24) in uniprot entity HNF4A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_175914.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0070026815).

BP6

Variant 20-44413724-C-T is Benign according to our data. Variant chr20-44413724-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44413724-C-T is described in Lovd as [Benign]. Variant chr20-44413724-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0251 (3818/152112) while in subpopulation AMR AF= 0.051 (779/15262). AF 95% confidence interval is 0.0481. There are 74 homozygotes in gnomad4. There are 1869 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3818 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.350C>T	p.Thr117Ile	missense_variant	4/10	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.350C>T	p.Thr117Ile	missense_variant	4/10	1	NM_175914.5	ENSP00000315180		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3815

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00587

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0507

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0134

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0416

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0297

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.0308

AC:

7718

AN:

250866

Hom.:

150

AF XY:

0.0300

AC XY:

4070

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.0454

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.0136

Gnomad SAS exome

AF:

0.0263

Gnomad FIN exome

AF:

0.0414

Gnomad NFE exome

AF:

0.0322

Gnomad OTH exome

AF:

0.0313

GnomAD4 exome

AF:

0.0300

AC:

43792

AN:

1461424

Hom.:

748

Cov.:

AF XY:

0.0298

AC XY:

21648

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00496

Gnomad4 AMR exome

AF:

0.0488

Gnomad4 ASJ exome

AF:

0.0253

Gnomad4 EAS exome

AF:

0.0110

Gnomad4 SAS exome

AF:

0.0256

Gnomad4 FIN exome

AF:

0.0420

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0251

AC:

3818

AN:

152112

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1869

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00585

Gnomad4 AMR

AF:

0.0510

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0128

Gnomad4 SAS

AF:

0.0284

Gnomad4 FIN

AF:

0.0416

Gnomad4 NFE

AF:

0.0297

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0282

Hom.:

193

Bravo

AF:

0.0245

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0328

AC:

282

ExAC

AF:

0.0310

AC:

3769

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0260

EpiControl

AF:

0.0262

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 309/13006=2.3% -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, 30297969, 25361053, 26503572) -

Familial hyperinsulinism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

rs1800961, a loss-of-function mutation in HNF4A is 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. This variant is also associated with increased risk of T2DM and periodontitis. -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 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. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: ClinVar=benign with 2 stars, Chicago and GeneDx call it benign . BP4 not being used because REVEL 0.426, BP6 no longer applied) -

Maturity-onset diabetes of the young type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

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

Eigen

Benign

0.062

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0070

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

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

1.2

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.43

Sift

Benign

0.25

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

Sift4G

Benign

0.20

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

Polyphen

0.0090, 0.0040, 0.0010

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

Vest4

0.34

MPC

0.68

ClinPred

0.028

GERP RS

5.2

Varity_R

0.33

gMVP

0.69

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