rs61737145

Positions:

• chr20-44428408-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000316673.9(HNF4A):​c.1137C>T​(p.Asn379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,614,170 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (30 hom.)
• Consequence: HNF4A ENST00000316673.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.60

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 20-44428408-C-T is Benign according to our data. Variant chr20-44428408-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44428408-C-T is described in Lovd as [Likely_benign]. Variant chr20-44428408-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00384 (585/152308) while in subpopulation NFE AF= 0.00572 (389/68028). AF 95% confidence interval is 0.00525. There are 4 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 585 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.1137C>T	p.Asn379=	synonymous_variant	9/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.1137C>T	p.Asn379=	synonymous_variant	9/10	1	NM_175914.5	ENSP00000315180

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152190 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00351 AC: 882 AN: 251346 Hom.: 3 AF XY: 0.00363 AC XY: 493 AN XY: 135868

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00589 AC: 8609 AN: 1461862 Hom.: 30 Cov.: 32 AF XY: 0.00568 AC XY: 4134 AN XY: 727232

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00692

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152308 Hom.: 4 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74486

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00472 Hom.: 0

Bravo AF: 0.00392

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	HNF4A: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Maturity onset diabetes mellitus in young Benign:2

Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs61737145 in MODY, yet. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2017	This alteration is classified as likely 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:2

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
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. -

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;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.8
DANN	Benign	0.84
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: rs61737145; hg19: chr20-43057048;