9-127818296-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1BS3_SupportingBP2

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in trans with the variant c.23T>C, p.Leu8Pro (PMID:19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID:25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211420/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 3 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: 0.638

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 links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3 link	c.1510G>A	p.Val504Met	missense_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 link	c.1510G>A	p.Val504Met	missense_variant	Exon 12 of 14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 link	c.964G>A	p.Val322Met	missense_variant	Exon 12 of 15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 link	n.1378-15C>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 link	c.1510G>A	p.Val504Met	missense_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4		P17813-1

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

448

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00119

AC:

298

AN:

250582

Hom.:

AF XY:

0.000981

AC XY:

133

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00894

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000451

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000709

AC:

1037

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000670

AC XY:

487

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00821

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000466

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.00296

AC:

451

AN:

152326

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00871

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.000737

Hom.:

Bravo

AF:

0.00322

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Benign:3

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in trans with the variant c.23T>C, p.Leu8Pro (PMID: 19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024). -

not specified

Benign:2

Jul 21, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENG: BP4, BS1, BS2 -

Dec 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25312062, 15024723, 22022569, 20981092, 19767588, 25637381, 22995991, 24055113) -

Haemorrhagic telangiectasia 1

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype

Benign:1

Jun 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary hemorrhagic telangiectasia

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.45

T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.41

N;.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.66

N;.;N

REVEL

Benign

0.24

Sift

Benign

0.22

T;.;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.84

P;.;.

Vest4

0.29

MVP

0.75

MPC

0.41

ClinPred

0.0056

GERP RS

2.1

Varity_R

0.069

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over