chr20-44355852-C-A

Variant names:

• chr20-44355852-C-A
• rs2146127862
• NM_175914.5:c.48C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_175914.5(HNF4A):​c.48C>A​(p.Tyr16*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0003447
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.752
• Publications: 3 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]

HNF4A Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• hyperinsulinism due to HNF4A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 117 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44355852-C-A is Pathogenic according to our data. Variant chr20-44355852-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1299753.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.48C>A	p.Tyr16*	stop_gained, splice_region_variant	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.48C>A	p.Tyr16*	stop_gained, splice_region_variant	Exon 1 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 05, 2021

Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.48C>A 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 5 informative meioses (PP1_Strong). A different nucleotide change at this nucleotide position that also results in the same pathogenic p.Tyr16Ter amino acid change has been identified by this laboratory (c.48C>G) (PS1_Strong). In summary, c.48C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Very Strong, PS1_Strong, 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	36
DANN	Uncertain	1.0
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.45	N
PhyloP100		0.75
Vest4		0.90
GERP RS		2.9
PromoterAI		-0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs2146127862; hg19: chr20-42984492; COSMIC: COSV107248541; COSMIC: COSV107248541;