rs1554810408

Variant names:

• chr9-127825791-GGCCGCCACTCGA-G
• rs1554810408
• NM_001114753.3:c.581_592delTCGAGTGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_001114753.3(ENG):​c.581_592delTCGAGTGGCGGC​(p.Leu194_Arg197del) variant causes a disruptive inframe deletion 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L194L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.55
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001114753.3.
• PP5: Variant 9-127825791-GGCCGCCACTCGA-G is Pathogenic according to our data. Variant chr9-127825791-GGCCGCCACTCGA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549762.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.581_592delTCGAGTGGCGGC	p.Leu194_Arg197del	disruptive_inframe_deletion	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.581_592delTCGAGTGGCGGC	p.Leu194_Arg197del	disruptive_inframe_deletion	Exon 5 of 14		NP_000109.1
ENG	NM_001278138.2	c.35_46delTCGAGTGGCGGC	p.Leu12_Arg15del	disruptive_inframe_deletion	Exon 5 of 15		NP_001265067.1
ENG	NM_001406715.1	c.581_592delTCGAGTGGCGGC	p.Leu194_Arg197del	disruptive_inframe_deletion	Exon 5 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.581_592delTCGAGTGGCGGC	p.Leu194_Arg197del	disruptive_inframe_deletion	Exon 5 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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Mar 28, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The ENG gene variant designated as NM_000118.3:c.589_592del12 is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 10.54 to 1 that this allele explains hereditary hemorrhagic telangiectasia in the family, providing evidence for pathogenicity of the variant (Thompson et al., 2003, PMID:1290079). We estimated a pretest probability of 90% supporting pathogenicity from PROVEAN computer algorithms. The ENG database from ARUP laboratories reported the variant in two affected relatives (one first-degree and one second-degree) of a proband (see Gedge et al., 2007, PMID:17384219 and http://www.arup.utah.edu/database/ENG/ENG_display.php). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 98% probability of pathogenicity, which is consistent with a classification of likely pathogenic. This variant is predicted to alter ENG function and cause hereditary hemorrhagic telangiectasia. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554810408; hg19: chr9-130588070;