9-127843154-G-T

Position:

• chr9-127843154-G-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.159C>A​(p.Cys53*) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C53C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.38

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 9-127843154-G-T is Pathogenic according to our data. Variant chr9-127843154-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 946806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127843154-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.159C>A	p.Cys53*	stop_gained	2/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.159C>A	p.Cys53*	stop_gained	2/14		NP_000109.1
ENG	NM_001406715.1	c.159C>A	p.Cys53*	stop_gained	2/8		NP_001393644.1
ENG	NM_001278138.2	c.-388C>A		5_prime_UTR_variant	2/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.159C>A	p.Cys53*	stop_gained	2/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.159C>A	p.Cys53*	stop_gained	2/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-388C>A		5_prime_UTR_variant	2/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2020	The ENG c.159C>A; p.Cys53Ter variant is reported in the literature in an individual affected with hereditary hemorrhagic telangiectasia (Letteboer 2005). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005;116(1-2):8-16. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This nonsense change has been observed in an individual affected with hereditary hemorrhagic telangiectasia (PMID: 15517393). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys53*) in the ENG gene. It is expected to result in an absent or disrupted protein product. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2017

The p.C53* pathogenic mutation (also known as c.159C>A), located in coding exon 2 of the ENG gene, results from a C to A substitution at nucleotide position 159. This changes the amino acid from a cysteine to a stop codon within coding exon 2. This mutation was identified in one individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.047	N
Vest4		0.79
GERP RS		-4.9

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: rs148475405; hg19: chr9-130605433;