rs1554810932

Positions:

• chr9-127829822-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.224del​(p.Pro75ArgfsTer6) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.462

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 18 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 9-127829822-CG-C is Pathogenic according to our data. Variant chr9-127829822-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 528051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.224del	p.Pro75ArgfsTer6	frameshift_variant	3/15	ENST00000373203.9
ENG	NM_000118.4	c.224del	p.Pro75ArgfsTer6	frameshift_variant	3/14
ENG	NM_001406715.1	c.224del	p.Pro75ArgfsTer6	frameshift_variant	3/8
ENG	NM_001278138.2	c.-323del		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.224del	p.Pro75ArgfsTer6	frameshift_variant	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.224del	p.Pro75ArgfsTer6	frameshift_variant	3/14	1		A2
ENG	ENST00000480266.6	c.-323del		5_prime_UTR_variant	3/15	2
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, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2023

This sequence change creates a premature translational stop signal (p.Pro75Argfs*6) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 21158752). ClinVar contains an entry for this variant (Variation ID: 528051). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

The c.224delC pathogenic mutation, located in coding exon 3 of the ENG gene, results from a deletion of one nucleotide at nucleotide position 224, causing a translational frameshift with a predicted alternate stop codon (p.P75Rfs*6). This mutation has been detected in a hereditary hemorrhagic telangiectasia (HHT) cohort and in an individual meeting clinical diagnostic criteria for HHT (McDonald J et al. Clin Genet. 2011;79(4):335-344; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554810932; hg19: chr9-130592101;