rs1800961

Variant names:

• chr20-44413724-C-T
• rs1800961
• NM_175914.5:c.350C>T

Variant summary

Our verdict is Benign. The variant received -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:11
• Conservation: PhyloP100: 7.87
• Publications: 299 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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 Benign/Likely_benign. ClinVar VariationId is 129240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3818 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.350C>T	p.Thr117Ile	missense_variant	Exon 4 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.350C>T	p.Thr117Ile	missense_variant	Exon 4 of 10	1	NM_175914.5	ENSP00000315180.4

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

GnomAD2 exomes AF: 0.0308 AC: 7718 AN: 250866 AF XY: 0.0300

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 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

African (AFR) AF: 0.00496 AC: 166 AN: 33476

American (AMR) AF: 0.0488 AC: 2181 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 662 AN: 26136

East Asian (EAS) AF: 0.0110 AC: 437 AN: 39692

South Asian (SAS) AF: 0.0256 AC: 2205 AN: 86224

European-Finnish (FIN) AF: 0.0420 AC: 2241 AN: 53398

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5766

European-Non Finnish (NFE) AF: 0.0308 AC: 34186 AN: 1111658

Other (OTH) AF: 0.0276 AC: 1667 AN: 60384

GnomAD4 genome AF: 0.0251 AC: 3818 AN: 152112 Hom.: 74 Cov.: 31 AF XY: 0.0251 AC XY: 1869 AN XY: 74344

African (AFR) AF: 0.00585 AC: 243 AN: 41526

American (AMR) AF: 0.0510 AC: 779 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.0128 AC: 66 AN: 5140

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4816

European-Finnish (FIN) AF: 0.0416 AC: 440 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2017 AN: 67998

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0283 Hom.: 356

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 05, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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% -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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. -

Type 2 diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Jul 16, 2015

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. -

Maturity-onset diabetes of the young type 1 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). 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
DEOGEN2	Benign	0.31	.;.;.;T;.;D;.
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
MutationAssessor	Benign	1.2	.;.;.;.;L;L;L
PhyloP100		7.9
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
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

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