9-127818173-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS1_SupportingBP2BP5

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID:18498373) which is classified as likely pathogenic (PMID:18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, 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 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_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252712/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 2 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1U:2B:7

Conservation

PhyloP100: 4.33

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 -3 ACMG points.

BP2

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

BP5

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

BS1

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.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 link	c.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 link	c.1087G>A	p.Gly363Ser	missense_variant	Exon 12 of 15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 link	n.1378-138C>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.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4		P17813-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000521

AC:

131

AN:

251296

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000528

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000666

AC:

973

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000771

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000361

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000507

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.12% (rs142896669, 54/35,428 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Sep 11, 2024	The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID: 18498373) which is classified as likely pathogenic (PMID: 18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, 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 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_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). -

Pulmonary hypertension, primary, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 probands, no segs in HGMD; ExAC: 0.2% (25/11560) Latino chromosomes -

Pulmonary arterial hypertension associated with congenital heart disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Wendy Chung Laboratory, Columbia University Medical Center

Jun 27, 2018

- -

ENG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2024

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

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

See Variant Classification Assertion Criteria. -

Hereditary hemorrhagic telangiectasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2025

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2017

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Uncertain

0.074

MutationAssessor

Benign

1.5

L;.;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.057

T;.;D

Sift4G

Benign

0.095

T;T;D

Polyphen

1.0

D;.;.

Vest4

0.48

MVP

0.88

MPC

0.76

ClinPred

0.068

GERP RS

5.2

Varity_R

0.29

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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