rs1555816642

chr20-44419771-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_175914.5(HNF4A):c.724del(p.Val242CysfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R241R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44419771-CG-C is Pathogenic according to our data. Variant chr20-44419771-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 447521.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44419771-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.724del	p.Val242CysfsTer39	frameshift_variant	7/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.724del	p.Val242CysfsTer39	frameshift_variant	7/10	1	NM_175914.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2018

The c.724delG pathogenic mutation, located in coding exon 7 of the HNF4A gene, results from a deletion of one nucleotide at nucleotide position 724, causing a translational frameshift with a predicted alternate stop codon (p.V242Cfs*39). This mutation was reported in a maturity-onset diabetes of the young family (Colclough K et al. Hum. Mutat., 2013 May;34:669-85). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 22, 2024

The c.724del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 242 in NM_175914.5, adding 39 novel amino acids before encountering a stop codon (p.(Val242Cysfs*39)). This variant, located in biologically-relevant exon 7 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.724del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP4, PM2_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555816642; hg19: chr20-43048411;