9-127825812-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5BA1

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.572G>A variant in ENG is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 191 (p.Gly191Asp). The filtering allele frequency (the lower threshold of the 95% CI of 1725/109328) of the c.572G>A variant in ENG is 0.01669 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). This variant has been observed in at least 2 patients with an alternate molecular basis for disease (patients also carry likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID:32573726, Internal lab contributors). The computational predictor REVEL gives a score of 0.275, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as 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: BA1, BP5 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA325327/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.0097 ( 9 hom., cov: 32)

Exomes 𝑓: 0.014 ( 171 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:18

Conservation

PhyloP100: 1.44

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP5

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ENG	NM_001114753.3 link	c.572G>A	p.Gly191Asp	missense_variant	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4 link	c.572G>A	p.Gly191Asp	missense_variant	Exon 5 of 14		NP_000109.1
ENG	NM_001278138.2 link	c.26G>A	p.Gly9Asp	missense_variant	Exon 5 of 15		NP_001265067.1
ENG	NM_001406715.1 link	c.572G>A	p.Gly191Asp	missense_variant	Exon 5 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 link	c.572G>A	p.Gly191Asp	missense_variant	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes

AF:

0.00972

AC:

1479

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00882

AC:

1897

AN:

215084

AF XY:

0.00878

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.00529

Gnomad ASJ exome

AF:

0.00916

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0143

AC:

20731

AN:

1445124

Hom.:

171

Cov.:

AF XY:

0.0138

AC XY:

9912

AN XY:

717402

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

33162

American (AMR)

AF:

0.00530

AC:

226

AN:

42660

Ashkenazi Jewish (ASJ)

AF:

0.00981

AC:

253

AN:

25782

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38902

South Asian (SAS)

AF:

0.00267

AC:

223

AN:

83654

European-Finnish (FIN)

AF:

0.00332

AC:

169

AN:

50838

Middle Eastern (MID)

AF:

0.00372

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.0172

AC:

19033

AN:

1104786

Other (OTH)

AF:

0.0121

AC:

720

AN:

59688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1289

2578

3867

5156

6445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00971

AC:

1479

AN:

152276

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

680

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41556

American (AMR)

AF:

0.00706

AC:

108

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0167

AC:

1138

AN:

67986

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.00911

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.00824

AC:

993

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 21, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: High frequency -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Telangiectasia, hereditary hemorrhagic, type 1

Benign:6

Mar 15, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_001114753.3: c.572G>A variant in ENG is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 191 (p.Gly191Asp). The filtering allele frequency (the lower threshold of the 95% CI of 1725/109328) of the c.572G>A variant in ENG is 0.01669 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). This variant has been observed in at least 2 patients with an alternate molecular basis for disease (patients also carry likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 32573726, Internal lab contributors). The computational predictor REVEL gives a score of 0.275, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as 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: BA1, BP5 (specification version 1.0.0; 1/4/2024). -

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

- -

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

BS1 +BP2+BP6 -

Oct 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Impact Genetics, Dynacare; LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1 -

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ENG: BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ENG-related disorder

Benign:1

May 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Jun 09, 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

Feb 04, 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

0.32

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.3

M;.;M

PhyloP100

1.4

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

D;.;D

REVEL

Benign

0.28

Sift

Benign

0.099

T;.;T

Sift4G

Uncertain

0.046

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.72

MVP

0.59

MPC

0.90

ClinPred

0.013

GERP RS

4.4

Varity_R

0.39

gMVP

0.70

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over