rs1554810507

Positions:

• chr9-127826636-CC-TT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001114753.3(ENG):​c.396_397delGGinsAA​(p.Val133Ile) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.162

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.396_397delGGinsAA	p.Val133Ile	missense_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.396_397delGGinsAA	p.Val133Ile	missense_variant			NP_000109.1
ENG	NM_001406715.1	c.396_397delGGinsAA	p.Val133Ile	missense_variant			NP_001393644.1
ENG	NM_001278138.2	c.-151_-150delGGinsAA		5_prime_UTR_variant	4/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.396_397delGGinsAA	p.Val133Ile	missense_variant		1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.396_397delGGinsAA	p.Val133Ile	missense_variant		1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-151_-150delGGinsAA		5_prime_UTR_variant	4/15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.296_297delGGinsAA		non_coding_transcript_exon_variant	3/4	3		ENSP00000519251.1

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ENG-related disease. This sequence change replaces valine with isoleucine at codon 133 of the ENG protein (p.Val133Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554810507; hg19: chr9-130588915;