rs1554809229

Variant names:

• chr9-127818121-TGGTCTTGAGACCC-T
• rs1554809229
• NM_001114753.3:c.1672_1684delGGGTCTCAAGACC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001114753.3(ENG):​c.1672_1684delGGGTCTCAAGACC​(p.Gly558ArgfsTer11) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G558G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000225032 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-127818121-TGGTCTTGAGACCC-T is Pathogenic according to our data. Variant chr9-127818121-TGGTCTTGAGACCC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 458340.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.1672_1684delGGGTCTCAAGACC	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1672_1684delGGGTCTCAAGACC	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	Exon 12 of 14		NP_000109.1
ENG	NM_001278138.2	c.1126_1138delGGGTCTCAAGACC	p.Gly376ArgfsTer11	frameshift_variant, splice_region_variant	Exon 12 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1378-182_1378-170delAGACCCGGTCTTG		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1672_1684delGGGTCTCAAGACC	p.Gly558ArgfsTer11	frameshift_variant, splice_region_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Mar 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in ENG are known to be pathogenic. This particular variant has been reported in the literature in individuals with hemorrhagic telangiectasia (PMID: 11440987, 21987708, 24196379). This sequence change deletes 13 nucleotides from exon 12 of the ENG mRNA (c.1672_1684delGGGTCTCAAGACC), causing a frameshift at codon 558. This creates a premature translational stop signal (p.Gly558Argfs*11) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554809229; hg19: chr9-130580400;