rs745975

Variant names:

• chr20-44406053-C-T
• rs745975
• NM_175914.5:c.50-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175914.5(HNF4A):​c.50-5C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00001241
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.18
• Publications: 37 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 -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 Benign/Likely_benign. ClinVar VariationId is 129239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.50-5C>T		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.50-5C>T		splice_region_variant, intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27706 AN: 152172 Hom.: 2828 Cov.: 33

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

GnomAD2 exomes AF: 0.197 AC: 49450 AN: 250434 AF XY: 0.205

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 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.: 33 AF XY: 0.225 AC XY: 163452 AN XY: 725146

African (AFR) AF: 0.0951 AC: 3175 AN: 33396

American (AMR) AF: 0.103 AC: 4587 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8093 AN: 26122

East Asian (EAS) AF: 0.181 AC: 7189 AN: 39688

South Asian (SAS) AF: 0.238 AC: 20496 AN: 86144

European-Finnish (FIN) AF: 0.194 AC: 10268 AN: 52982

Middle Eastern (MID) AF: 0.219 AC: 945 AN: 4308

European-Non Finnish (NFE) AF: 0.233 AC: 258317 AN: 1109682

Other (OTH) AF: 0.226 AC: 13573 AN: 60152

GnomAD4 genome AF: 0.182 AC: 27724 AN: 152290 Hom.: 2830 Cov.: 33 AF XY: 0.180 AC XY: 13384 AN XY: 74466

African (AFR) AF: 0.101 AC: 4200 AN: 41564

American (AMR) AF: 0.140 AC: 2147 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3470

East Asian (EAS) AF: 0.175 AC: 909 AN: 5184

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4824

European-Finnish (FIN) AF: 0.178 AC: 1889 AN: 10616

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15609 AN: 68008

Other (OTH) AF: 0.195 AC: 413 AN: 2114

Alfa AF: 0.216 Hom.: 5416

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10983627, 25266181) -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 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

- -

not specified Benign:3

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Maturity onset diabetes mellitus in young Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 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. -

Glycosuria Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.24
DANN	Benign	0.85
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs745975; hg19: chr20-43034693; COSMIC: COSV57381263; COSMIC: COSV57381263;