rs1800961

chr20-44413724-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 3815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.350C>T	p.Thr117Ile	missense_variant	4/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.350C>T	p.Thr117Ile	missense_variant	4/10	1	NM_175914.5

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3815 AN: 151994 Hom.: 72 Cov.: 31

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

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.: 32 AF XY: 0.0298 AC XY: 21648 AN XY: 727022

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.: 74 Cov.: 31 AF XY: 0.0251 AC XY: 1869 AN XY: 74344

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: 27

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0310 AC: 3769

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0260

EpiControl AF: 0.0262

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

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:2

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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. -

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 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. -

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	T
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
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	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
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	T
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

Other links and lift over

dbSNP: rs1800961; hg19: chr20-43042364; COSMIC: COSV57385393;