rs863223540

Positions:

• chr9-127824354-TTGTC-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.1080_1083delGACA​(p.Thr361fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.71

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]

ENG (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 9-127824354-TTGTC-T is Pathogenic according to our data. Variant chr9-127824354-TTGTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127824354-TTGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1080_1083delGACA	p.Thr361fs	frameshift_variant	8/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1080_1083delGACA	p.Thr361fs	frameshift_variant	8/14		NP_000109.1
ENG	NM_001278138.2	c.534_537delGACA	p.Thr179fs	frameshift_variant	8/15		NP_001265067.1
ENG	NM_001406715.1	c.1080_1083delGACA	p.Thr361fs	frameshift_variant	8/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1080_1083delGACA	p.Thr361fs	frameshift_variant	8/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1080_1083delGACA	p.Thr361fs	frameshift_variant	8/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.534_537delGACA	p.Thr179fs	frameshift_variant	8/15	2		ENSP00000479015.1
ENG	ENST00000486329.1	n.48_51delGACA		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	The ENG c.1080_1083delGACA; p.Thr361SerfsTer7 variant (rs863223540), also reported as c.1078_1081del, is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Gallione 1998, Nishida 2012, Snellings 2019). This variant is also reported in ClinVar (Variation ID: 213214). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it 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: Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. Snellings DA et al. Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. Am J Hum Genet. 2019 Nov 7;105(5):894-906. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	The c.1080_1083delGACA pathogenic variant in the ENG gene, also reported as c.1078_1081delGACA due to alternate nomenclature, has been identified previously in multiple members of a large family with HHT (Gallione et al., 1998). It has also been identified in several other unrelated individuals with HHT (Wehner et al., 2006; Bossler wt al., 2006; Olivieri et al., 2007; Nishida et al., 2012). Additionally, the c.1080_1083delGACA variant has not been observed in large population cohorts (Lek et al., 2016). The c.1080_1083delGACA variant causes a shift in reading frame starting at codon threonine 361, changing it to a serine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Thr361SerfsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other frameshift variants in the ENG gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2020	PVS1, PS4, PP1_Strong, PM2, PP4 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

The c.1080_1083delGACA pathogenic mutation, located in coding exon 8 of the ENG gene, results from a deletion of 4 nucleotides at nucleotide positions 1080 to 1083, causing a translational frameshift with a predicted alternate stop codon (p.T361Sfs*7). This mutation has been identified in multiple individuals with epistaxis, telangiectasias, and pulmonary arteriovenous malformations (Gallione CJ et al. Hum. Mutat., 1998;11:286-94; Wehner LE et al. Clin. Genet., 2006 Mar;69:239-45; Lee NP et al. J. Med. Genet., 2011 May;48:353-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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

Aug 16, 2023

This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 9554745, 16542389, 17786384, 21158752, 22991266). ClinVar contains an entry for this variant (Variation ID: 213214). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr361Serfs*7) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs863223540; hg19: chr9-130586633;