rs763475207

chr9-127818337-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):c.1469T>C(p.Leu490Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 2.44

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 9-127818337-A-G is Pathogenic according to our data. Variant chr9-127818337-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458338.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.1469T>C	p.Leu490Ser	missense_variant	12/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1404A>G		non_coding_transcript_exon_variant	3/6
ENG	NM_000118.4	c.1469T>C	p.Leu490Ser	missense_variant	12/14
ENG	NM_001278138.2	c.923T>C	p.Leu308Ser	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1469T>C	p.Leu490Ser	missense_variant	12/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1404A>G		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249768 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 04-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 490 of the ENG protein (p.Leu490Ser). This variant is present in population databases (rs763475207, gnomAD 0.0009%). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 16752392). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458338). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2016

The p.L490S variant (also known as c.1469T>C), located in coding exon 12 of the ENG gene, results from a T to C substitution at nucleotide position 1469. The leucine at codon 490 is replaced by serine, an amino acid with dissimilar properties. This variant was identified in multiple individuals of a family with epistaxis, telangiectasias, and/or arteriovenous malformation (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). Based on internal structural analysis, this variant disrupts the Zona pellucida domain and is anticipated to result in a decrease in structural stability (Lin SJ et al. Proc. Natl. Acad. Sci. U.S.A., 2011 Mar;108:5232-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.90		Gain of disorder (P = 0.0066);.;Gain of disorder (P = 0.0066);
MVP		0.99
MPC		0.95
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs763475207; hg19: chr9-130580616;