chr20-44355804-CA-C

Position:

• chr20-44355804-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PP4_Moderate PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (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-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea responsive) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with three informative meioses in one family (PP1; Internal lab contributors). In summary, c.1del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/1024): PVS1_Strong, PP4_Moderate, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2499225757/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 frameshift, start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.47

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.1del	p.Met1?	frameshift_variant, start_lost	1/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.1del	p.Met1?	frameshift_variant, start_lost	1/10	1	NM_175914.5	ENSP00000315180
HNF4A	ENST00000457232.5	c.1del	p.Met1?	frameshift_variant, start_lost	1/10	1		ENSP00000396216
HNF4A	ENST00000609795.5	c.1del	p.Met1?	frameshift_variant, start_lost	1/8	1		ENSP00000476609
HNF4A	ENST00000609262.5	c.-231del		5_prime_UTR_variant	1/4	1		ENSP00000476310

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 06, 2024

The c.1del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (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-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea responsive) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with three informative meioses in one family (PP1; Internal lab contributors). In summary, c.1del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/1024): PVS1_Strong, PP4_Moderate, PP1, PM2_Supporting. -

Maturity-onset diabetes of the young type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Exeter Molecular Genetics Laboratory

Oct 05, 2021

The c.1del variant in the HNF4 homeobox A gene, HNF4A, results in the loss of the initiation codon (p.Met1?) in exon 1 of the pancreatic specific HNF4A isoform NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Moderate; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual in our laboratory with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes. However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold. This individual has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sensitive so sulfonylureas) (PP4_Moderate). This variant segregated with diabetes, with three informative meioses in this individual's family (PP1_Supporting). In summary, c.1del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Moderate, PP4_Moderate, PP1_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-42984444;