rs1554810257

chr9-127825331-T-TC

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.715_716insG(p.Glu239GlyfsTer95) 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: 26)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.00300

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 9-127825331-T-TC is Pathogenic according to our data. Variant chr9-127825331-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 407137.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.715_716insG	p.Glu239GlyfsTer95	frameshift_variant	6/15	ENST00000373203.9
ENG	NM_000118.4	c.715_716insG	p.Glu239GlyfsTer95	frameshift_variant	6/14
ENG	NM_001278138.2	c.169_170insG	p.Glu57GlyfsTer95	frameshift_variant	6/15
ENG	NM_001406715.1	c.715_716insG	p.Glu239GlyfsTer95	frameshift_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.715_716insG	p.Glu239GlyfsTer95	frameshift_variant	6/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.715_716insG	p.Glu239GlyfsTer95	frameshift_variant	6/14	1		A2
ENG	ENST00000480266.6	c.169_170insG	p.Glu57GlyfsTer95	frameshift_variant	6/15	2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 407137; ClinVar); This variant is associated with the following publications: (PMID: 16752392, 29631995, 16690726, 31727138) -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

This sequence change creates a premature translational stop signal (p.Glu239Glyfs*95) 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 individual(s) with clinical features of ENG-related conditions (PMID: 16752392). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 407137). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The c.715dupG pathogenic mutation, located in coding exon 6 of the ENG gene, results from a duplication of G at nucleotide position 715, causing a translational frameshift with a predicted alternate stop codon (p.E239Gfs*95). This variant has been reported (also described as c.715_716insG, c.716_717insG) in individuals with hereditary hemorrhagic telangiectasia (HHT) (Bossler AD et al. Hum Mutat, 2006 Jul;27:667-75; Prigoda NL et al. J Med Genet, 2006 Sep;43:722-8; Zhu N et al. Circ Genom Precis Med, 2018 04;11:e001887). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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)		0.040		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: rs1554810257; hg19: chr9-130587610;