chr9-127819620-A-AC

Position:

• chr9-127819620-A-AC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.1311+1dupG variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.94

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]

ENG (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019221041 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 1, new splice context is: gggGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127819620-A-AC is Pathogenic according to our data. Variant chr9-127819620-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 458334.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1311+1dupG		splice_donor_variant, intron_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1311+1dupG		splice_donor_variant, intron_variant			NP_000109.1
ENG	NM_001278138.2	c.765+1dupG		splice_donor_variant, intron_variant			NP_001265067.1
LOC102723566	NR_136302.1	n.1568+912dupC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1311+1dupG		splice_donor_variant, intron_variant		1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). This variant has been reported in an individual affected with hereditary hemorrhagic telangiectasia (PMID: 17384219). This variant is also known as c.1311+1_2insG. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys438Glufs*63) in the ENG gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: 1
DS_DL_spliceai		0.90		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554809446; hg19: chr9-130581899;