9-127826640-CG-CGG

Variant names:

• chr9-127826640-C-CG
• NM_001114753.3:c.392dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.392dupC​(p.Val133GlyfsTer16) 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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0560

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 18 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 9-127826640-C-CG is Pathogenic according to our data. Variant chr9-127826640-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 2034993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.392dupC	p.Val133GlyfsTer16	frameshift_variant	Exon 4 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.392dupC	p.Val133GlyfsTer16	frameshift_variant	Exon 4 of 14		NP_000109.1
ENG	NM_001406715.1	c.392dupC	p.Val133GlyfsTer16	frameshift_variant	Exon 4 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-155dupC		5_prime_UTR_variant	Exon 4 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.392dupC	p.Val133GlyfsTer16	frameshift_variant	Exon 4 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.392dupC	p.Val133GlyfsTer16	frameshift_variant	Exon 4 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-155dupC		5_prime_UTR_variant	Exon 4 of 15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.292dupC		non_coding_transcript_exon_variant	Exon 3 of 4	3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ENG-related disorder Pathogenic:1

Sep 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ENG c.392dupC variant is predicted to result in a frameshift and premature protein termination (p.Val133Glyfs*16). To our knowledge, this variant has not been reported in the literature or a large population database, indicating this variant is rare. Frameshift variants in ENG are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Feb 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PVS1 -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val133Glyfs*16) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 2034993). For these reasons, this variant has been classified as Pathogenic. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130588919;