chr9-127815951-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1BP5BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID:15712270). The computational predictor REVEL gives a score of 0.188, 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, 22022569). 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, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211415/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

1
7
11

Clinical Significance

Likely benign reviewed by expert panel B:16

Conservation

PhyloP100: 2.10

Publications

16 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP5
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
ENGNM_001114753.3 linkc.1844C>T p.Ser615Leu missense_variant Exon 14 of 15 ENST00000373203.9 NP_001108225.1 P17813-1Q96CG0A0A024R878
ENGNM_000118.4 linkc.1844C>T p.Ser615Leu missense_variant Exon 14 of 14 NP_000109.1 P17813-2Q5T9B9
ENGNM_001278138.2 linkc.1298C>T p.Ser433Leu missense_variant Exon 14 of 15 NP_001265067.1 P17813Q96CG0F5GX88B7Z6Y5
LOC102723566NR_136302.1 linkn.-115G>A upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENGENST00000373203.9 linkc.1844C>T p.Ser615Leu missense_variant Exon 14 of 15 1 NM_001114753.3 ENSP00000362299.4 P17813-1

Frequencies

GnomAD3 genomes
AF:
0.00139
AC:
212
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00169
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00238
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.00154
AC:
345
AN:
224358
AF XY:
0.00153
show subpopulations
Gnomad AFR exome
AF:
0.000649
Gnomad AMR exome
AF:
0.000443
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000592
Gnomad FIN exome
AF:
0.00149
Gnomad NFE exome
AF:
0.00254
Gnomad OTH exome
AF:
0.00108
GnomAD4 exome
AF:
0.00206
AC:
2985
AN:
1447230
Hom.:
2
Cov.:
31
AF XY:
0.00202
AC XY:
1452
AN XY:
718594
show subpopulations
African (AFR)
AF:
0.000419
AC:
14
AN:
33378
American (AMR)
AF:
0.000472
AC:
20
AN:
42346
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25734
East Asian (EAS)
AF:
0.000281
AC:
11
AN:
39180
South Asian (SAS)
AF:
0.000955
AC:
80
AN:
83796
European-Finnish (FIN)
AF:
0.00144
AC:
74
AN:
51484
Middle Eastern (MID)
AF:
0.000176
AC:
1
AN:
5688
European-Non Finnish (NFE)
AF:
0.00245
AC:
2704
AN:
1105776
Other (OTH)
AF:
0.00135
AC:
81
AN:
59848
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
215
431
646
862
1077
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
100
200
300
400
500
<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:
0.00139
AC:
212
AN:
152346
Hom.:
0
Cov.:
33
AF XY:
0.00146
AC XY:
109
AN XY:
74492
show subpopulations
African (AFR)
AF:
0.000529
AC:
22
AN:
41586
American (AMR)
AF:
0.000392
AC:
6
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.00169
AC:
18
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00238
AC:
162
AN:
68014
Other (OTH)
AF:
0.000946
AC:
2
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
13
26
39
52
65
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00203
Hom.:
2
Bravo
AF:
0.00133
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00209
AC:
18
ExAC
AF:
0.00129
AC:
156

ClinVar

Significance: Likely benign
Submissions summary: Benign:16
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:6
Jan 01, 2018
NIHR Bioresource Rare Diseases, University of Cambridge
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

BS1 +BP2+BP6 -

May 28, 2019
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 31, 2018
SIB Swiss Institute of Bioinformatics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

This variant is interpreted as a Likely Benign, for Telangiectasia, hereditary hemorrhagic, type 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (http://exac.broadinstitute.org/variant/9-130578230-G-A). BS2-Supporting => BS2 downgraded in strength to supporting. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:15712270). -

Jun 28, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: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.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270). The computational predictor REVEL gives a score of 0.188, 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, 22022569). 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, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:5
-
Clinical Genetics, Academic Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ENG: BP4, BS1, BS2 -

Feb 06, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15712270, 24055113, 25637381, 22022569, 25312062, 30487145) -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 25, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: ExAC: 0.4% (108/26946) European chromosomes -

Haemorrhagic telangiectasia 1 Benign:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:research

- -

Hereditary hemorrhagic telangiectasia Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Mar 27, 2017
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
0.071
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;T;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.35
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.022
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M;.;M
PhyloP100
2.1
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-4.1
D;.;D
REVEL
Benign
0.19
Sift
Benign
0.065
T;.;T
Sift4G
Uncertain
0.053
T;D;T
Polyphen
0.11
B;.;.
Vest4
0.81
MVP
0.83
MPC
0.23
ClinPred
0.040
T
GERP RS
1.6
Varity_R
0.16
gMVP
0.71
Mutation Taster
=83/17
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs148002300; hg19: chr9-130578230; API