20-44355852-C-G

Position:

• chr20-44355852-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_Strong PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.48C>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 16 (p.(Tyr16*)) of NM_175914.5. This variant, located in biologically-relevant exon 1 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 segregated with diabetes/neonatal hyperinsulinism, with 13 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes or diazoxide-responsive hyperinsulinemic hypoglycemia; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, 16917892, 17407387, 18268044, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). In summary, c.48C>G 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, PP1_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409109938/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0003447
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.752

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 15 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.48C>G	p.Tyr16*	stop_gained, splice_region_variant	1/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.48C>G	p.Tyr16*	stop_gained, splice_region_variant	1/10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Exeter Molecular Genetics Laboratory	Oct 05, 2021	The c.48C>G variant in the HNF4 homeobox A gene, HNF4A, Results in the substitution of a tyrosine amino acid to a termination codon (p.Tyr16Ter) in exon 1 of the pancreatic specific HNF4A isoform NM_175914.5. This variant is predicted to generate an mRNA with a premature termination codon that would undergo nonsense mediated decay resulting in absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Very Strong; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified by our laboratory in an individual with clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate). This variant also segregated with diabetes in this family with 7 informative meioses (PP1_Strong). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 22, 2024

The c.48C>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 16 (p.(Tyr16*)) of NM_175914.5. This variant, located in biologically-relevant exon 1 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 segregated with diabetes/neonatal hyperinsulinism, with 13 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes or diazoxide-responsive hyperinsulinemic hypoglycemia; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, 16917892, 17407387, 18268044, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). In summary, c.48C>G 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, PP1_Strong, PP4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.47	N
Vest4		0.90
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.24

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: chr20-42984492;