rs1554809331

chr9-127818726-CTCT-CAC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001114753.3(ENG):c.1415_1417delinsGT(p.Gln472ArgfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: 1.24

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-127818727-TCT-AC is Pathogenic according to our data. Variant chr9-127818727-TCT-AC is described in ClinVar as [Pathogenic]. Clinvar id is 528066.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.1415_1417delinsGT	p.Gln472ArgfsTer19	frameshift_variant	11/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1568+16_1568+18delinsAC		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1415_1417delinsGT	p.Gln472ArgfsTer19	frameshift_variant	11/14
ENG	NM_001278138.2	c.869_871delinsGT	p.Gln290ArgfsTer19	frameshift_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1415_1417delinsGT	p.Gln472ArgfsTer19	frameshift_variant	11/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1568+16_1568+18delinsAC		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

Invitae

Nov 18, 2017

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 reported in several individuals affected with hereditary hemorrhagic telangiectasia (PMID: 10625079, 15907823, 17384219). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln472Argfs*19) in the ENG gene. It 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: rs1554809331; hg19: chr9-130581006;