rs1229650809

Variant names:

• chr20-44355806-T-A
• rs1229650809
• NM_175914.5:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44355806-T-A
• chr20-44355806-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PVS1_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.2T>A 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 an individual with a phenotype highly specific for HNF4A-monogenic diabetes (MPC > 50% and had a macrosomic infant with the variant with diazoxide-responsive hyperinsulinemic hypoglycemia (PP4_Moderate; Internal lab contributor). In summary, c.2T>A 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 10/11/2023): PVS1_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409109839/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 4.66
• 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: Likely_pathogenic. The variant received 7 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	NP_787110.2
	HNF4A	NM_001030003.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 10	NP_001025174.1	P41235-6
	HNF4A	NM_001030004.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 8	NP_001025175.1	P41235-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000457232.5	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000396216.1	P41235-6
	HNF4A	ENST00000609795.5	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000476609.1	P41235-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Benign	0.97
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
PhyloP100		4.7
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		0.81	P
Vest4		0.96
MutPred		0.98		Loss of stability (P = 0.019)
MVP		0.81
ClinPred		0.83	D
GERP RS		5.0
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1229650809; hg19: chr20-42984446;