rs736823

Variant names:

• chr20-44406143-C-T
• rs736823
• NM_175914.5:c.135C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_175914.5(HNF4A):​c.135C>T​(p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,613,868 control chromosomes in the GnomAD database, including 2,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (144 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2348 hom.)
• Consequence: HNF4A NM_175914.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.51

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 20-44406143-C-T is Benign according to our data. Variant chr20-44406143-C-T is described in ClinVar as [Benign]. Clinvar id is 129238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44406143-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.135C>T	p.Ala45Ala	synonymous_variant	Exon 2 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.135C>T	p.Ala45Ala	synonymous_variant	Exon 2 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5423 AN: 152224 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0342 AC: 8583 AN: 251160 Hom.: 230 AF XY: 0.0333 AC XY: 4524 AN XY: 135790

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0524 AC: 76563 AN: 1461526 Hom.: 2348 Cov.: 33 AF XY: 0.0507 AC XY: 36855 AN XY: 727070

Gnomad4 AFR exome AF: 0.00822

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0381

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00530

Gnomad4 FIN exome AF: 0.0427

Gnomad4 NFE exome AF: 0.0618

Gnomad4 OTH exome AF: 0.0478

GnomAD4 genome AF: 0.0356 AC: 5423 AN: 152342 Hom.: 144 Cov.: 33 AF XY: 0.0337 AC XY: 2511 AN XY: 74484

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0378

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0440

Gnomad4 NFE AF: 0.0569

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0489 Hom.: 287

Bravo AF: 0.0341

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0529

EpiControl AF: 0.0485

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hyperinsulinism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Maturity onset diabetes mellitus in young Benign:1

Mar 14, 2016

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs736823; hg19: chr20-43034783;