rs41322046

Positions:

chr9-127825812-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP5

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:16

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP5

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ENG	NM_001114753.3 linkuse as main transcript	c.572G>A	p.Gly191Asp	missense_variant	5/15	ENST00000373203.9
ENG	NM_000118.4 linkuse as main transcript	c.572G>A	p.Gly191Asp	missense_variant	5/14
ENG	NM_001278138.2 linkuse as main transcript	c.26G>A	p.Gly9Asp	missense_variant	5/15
ENG	NM_001406715.1 linkuse as main transcript	c.572G>A	p.Gly191Asp	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.572G>A	p.Gly191Asp	missense_variant	5/15	1	NM_001114753.3	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.572G>A	p.Gly191Asp	missense_variant	5/14	1		A2	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.26G>A	p.Gly9Asp	missense_variant	5/15	2
ENG	ENST00000462196.1 linkuse as main transcript	n.472G>A		non_coding_transcript_exon_variant	4/4	3

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

GnomAD3 exomes

AF:

0.00882

AC:

1897

AN:

215084

Hom.:

AF XY:

0.00878

AC XY:

1031

AN XY:

117418

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 SAS exome

AF:

0.00219

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

Gnomad4 AFR exome

AF:

0.00256

Gnomad4 AMR exome

AF:

0.00530

Gnomad4 ASJ exome

AF:

0.00981

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00267

Gnomad4 FIN exome

AF:

0.00332

Gnomad4 NFE exome

AF:

0.0172

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.00971

AC:

1479

AN:

152276

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

680

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0145

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:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: High frequency -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Telangiectasia, hereditary hemorrhagic, type 1

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Likely benign, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	BS1 +BP2+BP6 -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 14, 2022	- -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	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). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ENG: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

ENG-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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

MutationTaster

Benign

0.72

D;D;D;N

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

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

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