chr9-127829687-G-T

Position:

• chr9-127829687-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.360C>A​(p.Tyr120Ter) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y120Y) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0001413
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.04

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 9-127829687-G-T is Pathogenic according to our data. Variant chr9-127829687-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829687-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.360C>A	p.Tyr120Ter	stop_gained, splice_region_variant	3/15	ENST00000373203.9
ENG	NM_000118.4	c.360C>A	p.Tyr120Ter	stop_gained, splice_region_variant	3/14
ENG	NM_001406715.1	c.360C>A	p.Tyr120Ter	stop_gained, splice_region_variant	3/8
ENG	NM_001278138.2	c.-187C>A		splice_region_variant, 5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.360C>A	p.Tyr120Ter	stop_gained, splice_region_variant	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.360C>A	p.Tyr120Ter	stop_gained, splice_region_variant	3/14	1		A2
ENG	ENST00000480266.6	c.-187C>A		splice_region_variant, 5_prime_UTR_variant	3/15	2
ENG	ENST00000462196.1	n.118C>A		splice_region_variant, non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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	Oct 08, 2018	The ENG c.360C>A; p.Tyr120Ter variant (rs121918402), is reported in the literature in multiple individuals and families affected with hereditary hemorrhagic telangiectasia (Brusgaard 2004, Kjeldsen 2005, Torring 2014). This variant is reported in ClinVar (Variation ID: 16676), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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, the p.Tyr120Ter variant is considered to be pathogenic. References: Brusgaard K et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004 Dec;66(6):556-61. Kjeldsen AD et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med. 2005 Oct;258(4):349-55. Torring PM et al. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2014 Aug;86(2):123-33. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16676). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15521985). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr120*) 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.054	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.88
GERP RS		-7.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.17
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: rs121918402; hg19: chr9-130591966;