rs1060501421

Positions:

• chr9-127818160-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):​c.1646G>A​(p.Cys549Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C549G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.87

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127818161-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 995686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-127818160-C-T is Pathogenic according to our data. Variant chr9-127818160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1646G>A	p.Cys549Tyr	missense_variant	12/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1378-151C>T		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1646G>A	p.Cys549Tyr	missense_variant	12/14
ENG	NM_001278138.2	c.1100G>A	p.Cys367Tyr	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1646G>A	p.Cys549Tyr	missense_variant	12/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1378-151C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 19, 2022	DNA sequence analysis of the ENG gene demonstrated a sequence change, c.1646G>A, in exon 12 that results in an amino acid change, p.Cys549Tyr. This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Cys549Tyr change affects a highly conserved amino acid residue located in a domain of the ENG protein that is known to be functional. The p.Cys549Tyr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This amino acid change has been described in the literature in two first degree affected relatives with epistaxis, pulmonary arteriovenous malformation (AVM) and telangiectasia (PMID: 21158752). It has also been reported in an individual with idiopathic pulmonary arterial hypertension (PMID: 35346192). This sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 11, 2022	PP3, PM2_supporting, PS4_moderate -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 549 of the ENG protein (p.Cys549Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 20414677, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407135). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.0	D;.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.85		Gain of phosphorylation at C549 (P = 0.0573);.;Gain of phosphorylation at C549 (P = 0.0573);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.98

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: rs1060501421; hg19: chr9-130580439;