rs1060501412

Positions:

• chr9-127818719-CACAAAGCTCT-C

Variant summary

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

The NM_001114753.3(ENG):​c.1415_1424del​(p.Gln472ArgfsTer16) variant causes a frameshift change. 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:1
• Conservation: PhyloP100: 4.30

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 9-127818719-CACAAAGCTCT-C is Pathogenic according to our data. Variant chr9-127818719-CACAAAGCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 407117.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1415_1424del	p.Gln472ArgfsTer16	frameshift_variant	11/15	ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1	n.1568+9_1568+18del		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1415_1424del	p.Gln472ArgfsTer16	frameshift_variant	11/14		NP_000109.1
ENG	NM_001278138.2	c.869_878del	p.Gln290ArgfsTer16	frameshift_variant	11/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1415_1424del	p.Gln472ArgfsTer16	frameshift_variant	11/15	1	NM_001114753.3	ENSP00000362299	P2
	ENST00000439298.5	n.1568+9_1568+18del		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

Dec 13, 2016

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). This sequence change deletes 10 nucleotides from exon 11 of the ENG mRNA (c.1415_1424delAGAGCTTTGT), causing a frameshift at codon 472. This creates a premature translational stop signal (p.Gln472Argfs*16) 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: rs1060501412; hg19: chr9-130580998;