20-44355807-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_175914.5(HNF4A):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.87

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_175914.5 (HNF4A) was described as [Likely_pathogenic] in ClinVar as 689636
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44355807-G-A is Pathogenic according to our data. Variant chr20-44355807-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299751.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44355807-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.3G>A	p.Met1?	start_lost	1/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.3G>A	p.Met1?	start_lost	1/10	1	NM_175914.5
HNF4A	ENST00000457232.5	c.3G>A	p.Met1?	start_lost	1/10	1
HNF4A	ENST00000609795.5	c.3G>A	p.Met1?	start_lost	1/8	1
HNF4A	ENST00000609262.5	c.-229G>A		5_prime_UTR_variant	1/4	1

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.3G>A variant in the hepatocyte nuclear factor -4 alpha gene, HNF4A, results in a start loss at the initiation codon in NM_175914.4. 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). In addition, 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 negative diabetes autoantibodies (PP4_Moderate; PMID: 30977832, internal lab contributors). In summary, c.3G>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, PM2_Supporting, PP4_Moderate. -

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.3G>A 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 two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID:21683639, PMID:30977832). However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold. 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; PMID:30977832). This variant also segregated with diabetes, with two informative meioses in the published family (PMID:21683639) but this is an insufficient number of meiosis to meet PP1 criteria. A different variant at that also results in the loss of the initiation codon has been identified by our laboratory and classified as likely pathogenic (PS1_Supporting). In summary, c.3G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Moderate, PS1_Supporting, PP4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.34	N;.;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.;D
Sift4G	Benign	0.29	T;T;T
Polyphen		0.66, 0.39	.;P;B
Vest4		0.94
MutPred		0.99		Gain of catalytic residue at S3 (P = 0.0992);Gain of catalytic residue at S3 (P = 0.0992);Gain of catalytic residue at S3 (P = 0.0992);
MVP		0.97
ClinPred		0.93	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: chr20-42984447;