rs1554810928

Positions:

• chr9-127829817-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000373203.9(ENG):​c.229del​(p.Gln77SerfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG ENST00000373203.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.98

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127829817-TG-T is Pathogenic according to our data. Variant chr9-127829817-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 458344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.229del	p.Gln77SerfsTer4	frameshift_variant	3/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.229del	p.Gln77SerfsTer4	frameshift_variant	3/14		NP_000109.1
ENG	NM_001406715.1	c.229del	p.Gln77SerfsTer4	frameshift_variant	3/8		NP_001393644.1
ENG	NM_001278138.2	c.-318del		5_prime_UTR_variant	3/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.229del	p.Gln77SerfsTer4	frameshift_variant	3/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.229del	p.Gln77SerfsTer4	frameshift_variant	3/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.-318del		5_prime_UTR_variant	3/15	2		ENSP00000479015
ENG	ENST00000462196.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

ENG-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The ENG c.229delC variant is predicted to result in a frameshift and premature protein termination (p.Gln77Serfs*4). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift variants in ENG are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in ENG are known to be pathogenic (PMID: 20656886, 15879500, 22385575). This sequence change deletes 1 nucleotide in exon 3 of the ENG mRNA (c.229delC), causing a frameshift at codon 77. This creates a premature translational stop signal (p.Gln77Serfs*4) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554810928; hg19: chr9-130592096;