9-127818222-CGG-CG

Variant names:

• chr9-127818222-CG-C
• rs1554809253
• NM_001114753.3:c.1583delC

Variant summary

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

The NM_001114753.3(ENG):​c.1583delC​(p.Pro528ArgfsTer24) 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:1
• Conservation: PhyloP100: -0.331

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]

ENSG00000225032 (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 9-127818222-CG-C is Pathogenic according to our data. Variant chr9-127818222-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 523407.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1583delC	p.Pro528ArgfsTer24	frameshift_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1583delC	p.Pro528ArgfsTer24	frameshift_variant	Exon 12 of 14		NP_000109.1
ENG	NM_001278138.2	c.1037delC	p.Pro346ArgfsTer24	frameshift_variant	Exon 12 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1378-86delG		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1583delC	p.Pro528ArgfsTer24	frameshift_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary arteriovenous malformation;C1857699:Palate telangiectasia;C3809715:Spontaneous, recurrent epistaxis;C4022018:Telangiectasia of the skin;C4025877:Oral cavity telangiectasia Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554809253; hg19: chr9-130580501;