rs1554810041

chr9-127824326-A-AC

Variant summary

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

The NM_001114753.3(ENG):c.1111_1112insG(p.Val371GlyfsTer25) 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: 30)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.23

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]

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 9-127824326-A-AC is Pathogenic according to our data. Variant chr9-127824326-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 458325.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.1111_1112insG	p.Val371GlyfsTer25	frameshift_variant	8/15	ENST00000373203.9
ENG	NM_000118.4	c.1111_1112insG	p.Val371GlyfsTer25	frameshift_variant	8/14
ENG	NM_001278138.2	c.565_566insG	p.Val189GlyfsTer25	frameshift_variant	8/15
ENG	NM_001406715.1	c.1111_1112insG	p.Val371GlyfsTer28	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1111_1112insG	p.Val371GlyfsTer25	frameshift_variant	8/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.1111_1112insG	p.Val371GlyfsTer25	frameshift_variant	8/14	1		A2
ENG	ENST00000480266.6	c.565_566insG	p.Val189GlyfsTer25	frameshift_variant	8/15	2
ENG	ENST00000486329.1	n.79_80insG		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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

Jul 25, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 458325). This premature translational stop signal has been observed in individual(s) with hemorrhagic telangiectasia (PMID: 8595426, 12673790, 21158752). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val371Glyfs*25) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1554810041; hg19: chr9-130586605;