chr9-127815990-AT-A

Variant names:

• chr9-127815990-AT-A
• rs1085307435
• NM_001114753.3:c.1804delA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001114753.3(ENG):​c.1804delA​(p.Ile602SerfsTer70) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. I602I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.16

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0875 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127815990-AT-A is Pathogenic according to our data. Variant chr9-127815990-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 426046.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1804delA	p.Ile602SerfsTer70	frameshift_variant	Exon 14 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1804delA	p.Ile602SerfsTer38	frameshift_variant	Exon 14 of 14		NP_000109.1
ENG	NM_001278138.2	c.1258delA	p.Ile420SerfsTer70	frameshift_variant	Exon 14 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.-75delT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1804delA	p.Ile602SerfsTer70	frameshift_variant	Exon 14 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1804delA	p.Ile602SerfsTer38	frameshift_variant	Exon 14 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.1258delA	p.Ile420SerfsTer70	frameshift_variant	Exon 14 of 15	2		ENSP00000479015.1
ENSG00000225032	ENST00000439298.5	n.-75delT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1085307435; hg19: chr9-130578269;