chr9-127843183-A-C

Position:

• chr9-127843183-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001114753.3(ENG):​c.130T>G​(p.Tyr44Asp) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.130T>G	p.Tyr44Asp	missense_variant	2/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.130T>G	p.Tyr44Asp	missense_variant	2/14		NP_000109.1
ENG	NM_001406715.1	c.130T>G	p.Tyr44Asp	missense_variant	2/8		NP_001393644.1
ENG	NM_001278138.2	c.-417T>G		5_prime_UTR_variant	2/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.130T>G	p.Tyr44Asp	missense_variant	2/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.130T>G	p.Tyr44Asp	missense_variant	2/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.-417T>G		5_prime_UTR_variant	2/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2019

This sequence change replaces tyrosine with aspartic acid at codon 44 of the ENG protein (p.Tyr44Asp). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ENG-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.80
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.47		Gain of disorder (P = 0.0203);Gain of disorder (P = 0.0203);
MVP		0.83
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.88

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: rs1554812271; hg19: chr9-130605462;