rs1085307433

chr9-127818733-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001114753.3(ENG):c.1410del(p.Gln471SerfsTer20) 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: 32)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -2.75

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 9-127818733-GC-G is Pathogenic according to our data. Variant chr9-127818733-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 426044.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1410del	p.Gln471SerfsTer20	frameshift_variant	11/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1568+26del		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1410del	p.Gln471SerfsTer20	frameshift_variant	11/14
ENG	NM_001278138.2	c.864del	p.Gln289SerfsTer20	frameshift_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1410del	p.Gln471SerfsTer20	frameshift_variant	11/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1568+26del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2018

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 variant has been observed in individuals affected with hereditary haemorrhagic telangiectasia (PMID: 15024723, 15115879, Invitae). This variant is also known as del470G and p.Gly470fsX490 in the literature. ClinVar contains an entry for this variant (Variation ID: 426044). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln471Serfs*20) in the ENG gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1085307433; hg19: chr9-130581012;