chr9-127824973-G-A

Variant names:

• chr9-127824973-G-A
• rs727503038
• NM_001114753.3:c.818C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001114753.3(ENG):​c.818C>T​(p.Thr273Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: ENG NM_001114753.3 missense, splice_region
• Scores: Splicing: ADA: 0.02901
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.74

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a disulfide_bond (size 88) in uniprot entity EGLN_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	Exon 7 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	Exon 7 of 14		NP_000109.1
ENG	NM_001278138.2	c.272C>T	p.Thr91Ile	missense_variant, splice_region_variant	Exon 7 of 15		NP_001265067.1
ENG	NM_001406715.1	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	Exon 7 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	Exon 7 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	Exon 7 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.272C>T	p.Thr91Ile	missense_variant, splice_region_variant	Exon 7 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemorrhagic telangiectasia Uncertain:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 273 of the ENG protein (p.Thr273Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 163407). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.0	M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Benign	0.28
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.96	D;.;.
Vest4		0.34
MutPred		0.74		Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);
MVP		0.62
MPC		0.68
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.28
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.029
dbscSNV1_RF	Benign	0.36
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: rs727503038; hg19: chr9-130587252;