20-44419795-G-T

Variant names:

• chr20-44419795-G-T
• rs781364316
• NM_175914.5:c.745G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.745G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 249 (p.(Glu249Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and 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 was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). In summary, c.745G>T 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107472/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• 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 10 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.745G>T	p.Glu249*	stop_gained	Exon 7 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.745G>T	p.Glu249*	stop_gained	Exon 7 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Aug 30, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.745G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 249 (p.(Glu249Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and 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 was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). In summary, c.745G>T 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

Jul 28, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.93
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781364316; hg19: chr20-43048435; COSMIC: COSV57384440;