rs863223539

Positions:

• chr9-127817175-A-T

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.1715T>A​(p.Leu572*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.34

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]

ENSG00000225032 (HGNC:):

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 9-127817175-A-T is Pathogenic according to our data. Variant chr9-127817175-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 213213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1715T>A	p.Leu572*	stop_gained	13/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1715T>A	p.Leu572*	stop_gained	13/14		NP_000109.1
ENG	NM_001278138.2	c.1169T>A	p.Leu390*	stop_gained	13/15		NP_001265067.1
LOC102723566	NR_136302.1	n.1110A>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1715T>A	p.Leu572*	stop_gained	13/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1715T>A	p.Leu572*	stop_gained	13/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.1169T>A	p.Leu390*	stop_gained	13/15	2		ENSP00000479015.1
ENSG00000225032	ENST00000439298.5	n.1110A>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2020	Reported previously in two individuals from one family with pulmonary and cerebral arteriovenous malformations (Pacquet et al., 2001); Published functional studies demonstrate a damaging effect (Paquet et al., 2001); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 54 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 15907823, 11440987) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2024	PM2, PS3_supporting, PS4_moderate, PVS1 -

ENG-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2024

The ENG c.1715T>A variant is predicted to result in premature protein termination (p.Leu572*). This variant has been reported in an individual with hereditary hemorrhagic telangiectasia (referred to as T1715A in Paquet et al. 2001. PubMed ID: 11440987). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ENG are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2022

The p.L572* pathogenic mutation (also known as c.1715T>A), located in coding exon 13 of the ENG gene, results from a T to A substitution at nucleotide position 1715. This changes the amino acid from a leucine to a stop codon within coding exon 13. This mutation was described in a family with both pulmonary and cerebral arteriovenous malformations. In addition, in vitro studies suggested impaired processing and undetectable level of truncated protein (Paquet ME et al. Hum. Mol. Genet., 2001 Jun;10:1347-57). 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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2023

This premature translational stop signal has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 11440987; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu572*) in the ENG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the ENG protein. This variant is also known as delta571. ClinVar contains an entry for this variant (Variation ID: 213213). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ENG function (PMID: 11440987). This variant disrupts the C-terminus of the ENG protein. Other variant(s) that disrupt this region (p.Pro577Argfs*42, p.Ile602Serfs*38) have been observed in individuals with ENG-related conditions (PMID: 21158752, 23919827). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.45	N
Vest4		0.74
GERP RS		3.6

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: rs863223539; hg19: chr9-130579454;