chr9-127843183-A-G

Variant names:

• chr9-127843183-A-G
• NM_001114753.3:c.130T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001114753.3(ENG):​c.130T>C​(p.Tyr44His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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, multiple submitters, no conflicts U:2
• 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 2 ACMG points.

• 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.130T>C	p.Tyr44His	missense_variant	Exon 2 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.130T>C	p.Tyr44His	missense_variant	Exon 2 of 14		NP_000109.1
ENG	NM_001406715.1	c.130T>C	p.Tyr44His	missense_variant	Exon 2 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-417T>C		5_prime_UTR_variant	Exon 2 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.130T>C	p.Tyr44His	missense_variant	Exon 2 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.130T>C	p.Tyr44His	missense_variant	Exon 2 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-417T>C		5_prime_UTR_variant	Exon 2 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Mar 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Hereditary hemorrhagic telangiectasia Uncertain:1

Aug 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces tyrosine with histidine at codon 44 of the ENG protein (p.Tyr44His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.45		Gain of disorder (P = 0.0254);Gain of disorder (P = 0.0254);
MVP		0.62
MPC		0.91
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.50
gMVP		0.73

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: chr9-130605462;