rs1085307431

Positions:

• chr9-127825259-A-C
• chr9-127825259-A-G
• chr9-127825259-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001114753.3(ENG):​c.788T>G​(p.Ile263Ser) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I263T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 27)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 14 ACMG points.

• PS1: Transcript NM_001114753.3 (ENG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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, 0.982
• PP5: Variant 9-127825259-A-C is Pathogenic according to our data. Variant chr9-127825259-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1330519.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.788T>G	p.Ile263Ser	missense_variant	6/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.788T>G	p.Ile263Ser	missense_variant	6/14		NP_000109.1
ENG	NM_001278138.2	c.242T>G	p.Ile81Ser	missense_variant	6/15		NP_001265067.1
ENG	NM_001406715.1	c.788T>G	p.Ile263Ser	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>G	p.Ile263Ser	missense_variant	6/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.788T>G	p.Ile263Ser	missense_variant	6/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.242T>G	p.Ile81Ser	missense_variant	6/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 20, 2021

The ENG c.788T>G; p.Ile263Ser variant, is reported in the literature in an individual with symptoms of HHT (Richards-Yutz 2010). Other variants at this codon (Ile263Asn, Ile263Thr) are also reported in individuals and families with HHT (Chen 2013, Lesca 2004). The p.Ile263Ser variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 263 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. 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. Lesca G et al. French Rendu-Osler Network. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.83		Loss of stability (P = 0.0137);.;Loss of stability (P = 0.0137);
MVP		0.96
MPC		0.98
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130587538;