rs12042

Positions:

• chr9-127824907-G-A
• chr9-127824907-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.884C>T​(p.Thr295Ile) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.47

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 88) in uniprot entity EGLN_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127824907-G-A is Pathogenic according to our data. Variant chr9-127824907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 571294.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.884C>T	p.Thr295Ile	missense_variant	7/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.884C>T	p.Thr295Ile	missense_variant	7/14		NP_000109.1
ENG	NM_001278138.2	c.338C>T	p.Thr113Ile	missense_variant	7/15		NP_001265067.1
ENG	NM_001406715.1	c.884C>T	p.Thr295Ile	missense_variant	7/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.884C>T	p.Thr295Ile	missense_variant	7/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.884C>T	p.Thr295Ile	missense_variant	7/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.338C>T	p.Thr113Ile	missense_variant	7/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 10, 2023

ClinVar contains an entry for this variant (Variation ID: 571294). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the ENG protein (p.Thr295Ile). 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 expected to disrupt ENG protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.022	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.73
MutPred		0.59		Loss of phosphorylation at T295 (P = 0.0266);.;Loss of phosphorylation at T295 (P = 0.0266);
MVP		0.64
MPC		0.83
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.32
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs12042; hg19: chr9-130587186;