9-127826659-A-T

Variant names:

• chr9-127826659-A-T
• rs750115837
• NM_001114753.3:c.374T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001114753.3(ENG):​c.374T>A​(p.Val125Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.38
• Publications: 3 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 9-127826659-A-T is Pathogenic according to our data. Variant chr9-127826659-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429941.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.374T>A	p.Val125Asp	missense_variant	Exon 4 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.374T>A	p.Val125Asp	missense_variant	Exon 4 of 14		NP_000109.1
ENG	NM_001406715.1	c.374T>A	p.Val125Asp	missense_variant	Exon 4 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-173T>A		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.374T>A	p.Val125Asp	missense_variant	Exon 4 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Mar 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16611099, 12667943, 35281255, 22022569, 16752392, 28564608, 11440987) -

Hereditary hemorrhagic telangiectasia Uncertain:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 125 of the ENG protein (p.Val125Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ENG-related conditions (PMID: 11440987). ClinVar contains an entry for this variant (Variation ID: 429941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ENG protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ENG function (PMID: 22022569). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		1.4
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.73	P;.
Vest4		0.86
MutPred		0.63		Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);
MVP		0.97
MPC		0.82
ClinPred		0.92	D
GERP RS		4.0
Varity_R		0.87
gMVP		0.78
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs750115837; hg19: chr9-130588938;