rs1060501415

Variant names:

• chr9-127825334-A-T
• rs1060501415
• NM_001114753.3:c.713T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001114753.3(ENG):​c.713T>A​(p.Val238Glu) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 26)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.74

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 7 ACMG points.

• PM1: In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 9-127825334-A-T is Pathogenic according to our data. Variant chr9-127825334-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407121.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 14		NP_000109.1
ENG	NM_001278138.2	c.167T>A	p.Val56Glu	missense_variant	Exon 6 of 15		NP_001265067.1
ENG	NM_001406715.1	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.713T>A	p.Val238Glu	missense_variant	Exon 6 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.167T>A	p.Val56Glu	missense_variant	Exon 6 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 12, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_supporting, PS4_moderate -

Aug 22, 2024

GeneDx

Significance: Uncertain significance

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: 20414677) -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 238 of the ENG protein (p.Val238Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 20414677; internal data). ClinVar contains an entry for this variant (Variation ID: 407121). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ENG protein function. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Uncertain:1

Sep 05, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V238E variant (also known as c.713T>A), located in coding exon 6 of the ENG gene, results from a T to A substitution at nucleotide position 713. The valine at codon 238 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was described in individual with possible hereditary hemorrhagic telangiectasia based on pulmonary AVMs and a family history. Reportedly, the alteration segregated with disease in the family; however, the number of family members, clinical information on additional relatives, and the nature of the familial relationships were not described (Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;T;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.94
MutPred		0.67		Gain of disorder (P = 0.009);.;Gain of disorder (P = 0.009);
MVP		0.88
MPC		0.96
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.82
gMVP		0.88

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: rs1060501415; hg19: chr9-130587613;