dbSNP rs201768056: ENG:p.Val588Leu (chr9-127816033-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001114753.3(ENG):c.1762G>C(p.Val588Leu) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V588I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.485

Publications

2 publications found

Variant links:

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]

ENG Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile polyposis syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENG links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09086117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3 link	c.1762G>C	p.Val588Leu	missense_variant	Exon 14 of 15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 link	c.1762G>C	p.Val588Leu	missense_variant	Exon 14 of 14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 link	c.1216G>C	p.Val406Leu	missense_variant	Exon 14 of 15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 link	n.-33C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 link	c.1762G>C	p.Val588Leu	missense_variant	Exon 14 of 15	1	NM_001114753.3	ENSP00000362299.4		P17813-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

242778

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725036

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

85592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111116

Other (OTH)

AF:

0.00

AC:

AN:

60192

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Uncertain

0.42

T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L

PhyloP100

0.48

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.018

Sift

Benign

0.15

T;.;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0090

B;.;.

Vest4

0.26

MutPred

0.24

Loss of methylation at K585 (P = 0.0682);.;Loss of methylation at K585 (P = 0.0682);

MVP

0.41

MPC

0.21

ClinPred

0.062

GERP RS

-0.0068

Varity_R

0.098

gMVP

0.63

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over