20-44355805-A-G

Variant names:

• chr20-44355805-A-G
• NM_175914.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PS4_Moderate PP1_Strong PVS1_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1A>G variant in the hepatocyte 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 (PVS1_Strong; PMID:23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; Internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; Internal lab contributors). In summary, c.1A>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): PP1_Strong, PVS1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409109837/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 5.47
• Publications: 0 publications found

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]

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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 rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Jun 09, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1A>G variant in the hepatocyte 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 (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; Internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; Internal lab contributors). In summary, c.1A>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): PP1_Strong, PVS1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.59	D
PhyloP100		5.5
PROVEAN	Benign	-0.26	N;.;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;D
Sift4G	Benign	0.70	T;T;T
Polyphen		0.45, 0.22	.;B;B
Vest4		0.97
MutPred		0.99		Gain of glycosylation at S3 (P = 0.2274);Gain of glycosylation at S3 (P = 0.2274);Gain of glycosylation at S3 (P = 0.2274);
MVP		0.94
ClinPred		0.90	D
GERP RS		5.0
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=5/195	disease causing

Splicing

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

Other links and lift over

hg19: chr20-42984445;