rs1554809229

Positions:

• chr9-127818121-TGGTCTTGAGACCC-T

Variant summary

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

The NM_001114753.3(ENG):​c.1672_1684del​(p.Gly558ArgfsTer11) variant causes a frameshift, splice region 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 (★). Synonymous variant affecting the same amino acid position (i.e. G558G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.80

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 9-127818121-TGGTCTTGAGACCC-T is Pathogenic according to our data. Variant chr9-127818121-TGGTCTTGAGACCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 458340.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.1672_1684del	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	12/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1378-182_1378-170del		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1672_1684del	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	12/14
ENG	NM_001278138.2	c.1126_1138del	p.Gly376ArgfsTer11	frameshift_variant, splice_region_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1672_1684del	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	12/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1378-182_1378-170del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic. This particular variant has been reported in the literature in individuals with hemorrhagic telangiectasia (PMID: 11440987, 21987708, 24196379). This sequence change deletes 13 nucleotides from exon 12 of the ENG mRNA (c.1672_1684delGGGTCTCAAGACC), causing a frameshift at codon 558. This creates a premature translational stop signal (p.Gly558Argfs*11) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554809229; hg19: chr9-130580400;