9-127825259-A-T

Position:

• chr9-127825259-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001114753.3(ENG):​c.788T>A​(p.Ile263Asn) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I263S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 27)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.17

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 8) in uniprot entity EGLN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.788T>A	p.Ile263Asn	missense_variant	6/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.788T>A	p.Ile263Asn	missense_variant	6/14		NP_000109.1
ENG	NM_001278138.2	c.242T>A	p.Ile81Asn	missense_variant	6/15		NP_001265067.1
ENG	NM_001406715.1	c.788T>A	p.Ile263Asn	missense_variant	6/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.788T>A	p.Ile263Asn	missense_variant	6/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.788T>A	p.Ile263Asn	missense_variant	6/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.242T>A	p.Ile81Asn	missense_variant	6/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 24, 2017

The ENG c.788T>A;p.Ile263Asn variant has been described in individuals with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension (Chen 2013, Machado 2015). The variant is listed in the ClinVar database (Variation ID: 426042), but not in the dbSNP variant database or the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant cannot be classified with certainty. References: Chen YJ et al. Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. Eur J Clin Invest. 2013 Oct;43(10):1016-24. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.82		Loss of stability (P = 0.0196);.;Loss of stability (P = 0.0196);
MVP		0.65
MPC		1.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.94

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: rs1085307431; hg19: chr9-130587538;