rs36092484

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001114753.3(ENG):​c.1060C>T​(p.Leu354Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0149 in 1,614,118 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 181 hom., cov: 30)
Exomes 𝑓: 0.013 ( 299 hom. )

Consequence

ENG
NM_001114753.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.21

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 9-127824378-G-A is Benign according to our data. Variant chr9-127824378-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ENGNM_001114753.3 linkc.1060C>T p.Leu354Leu synonymous_variant Exon 8 of 15 ENST00000373203.9 NP_001108225.1 P17813-1Q96CG0A0A024R878
ENGNM_000118.4 linkc.1060C>T p.Leu354Leu synonymous_variant Exon 8 of 14 NP_000109.1 P17813-2Q5T9B9
ENGNM_001278138.2 linkc.514C>T p.Leu172Leu synonymous_variant Exon 8 of 15 NP_001265067.1 P17813Q96CG0F5GX88B7Z6Y5
ENGNM_001406715.1 linkc.1060C>T p.Leu354Leu synonymous_variant Exon 8 of 8 NP_001393644.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENGENST00000373203.9 linkc.1060C>T p.Leu354Leu synonymous_variant Exon 8 of 15 1 NM_001114753.3 ENSP00000362299.4 P17813-1

Frequencies

GnomAD3 genomes
AF:
0.0334
AC:
5084
AN:
152110
Hom.:
180
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0890
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0147
Gnomad ASJ
AF:
0.00433
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00559
Gnomad FIN
AF:
0.0310
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0111
Gnomad OTH
AF:
0.0235
GnomAD2 exomes
AF:
0.0161
AC:
4056
AN:
251414
AF XY:
0.0144
show subpopulations
Gnomad AFR exome
AF:
0.0929
Gnomad AMR exome
AF:
0.00604
Gnomad ASJ exome
AF:
0.00427
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.0320
Gnomad NFE exome
AF:
0.0124
Gnomad OTH exome
AF:
0.0122
GnomAD4 exome
AF:
0.0129
AC:
18907
AN:
1461890
Hom.:
299
Cov.:
33
AF XY:
0.0124
AC XY:
8993
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.102
AC:
3418
AN:
33480
American (AMR)
AF:
0.00715
AC:
320
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00348
AC:
91
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.00365
AC:
315
AN:
86258
European-Finnish (FIN)
AF:
0.0308
AC:
1645
AN:
53418
Middle Eastern (MID)
AF:
0.00971
AC:
56
AN:
5768
European-Non Finnish (NFE)
AF:
0.0110
AC:
12208
AN:
1112010
Other (OTH)
AF:
0.0141
AC:
852
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1148
2295
3443
4590
5738
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
490
980
1470
1960
2450
<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:
0.0334
AC:
5092
AN:
152228
Hom.:
181
Cov.:
30
AF XY:
0.0333
AC XY:
2478
AN XY:
74452
show subpopulations
African (AFR)
AF:
0.0889
AC:
3693
AN:
41522
American (AMR)
AF:
0.0146
AC:
224
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00433
AC:
15
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5186
South Asian (SAS)
AF:
0.00539
AC:
26
AN:
4828
European-Finnish (FIN)
AF:
0.0310
AC:
329
AN:
10606
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.0111
AC:
753
AN:
68006
Other (OTH)
AF:
0.0232
AC:
49
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
233
466
700
933
1166
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
54
108
162
216
270
<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:
0.0189
Hom.:
110
Bravo
AF:
0.0360
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.00883
EpiControl
AF:
0.00830

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 28, 2014
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. -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Leu354Leu in exon 8 of ENG: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 9.7% (427/4406) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs36092484). -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

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

- -

Cardiovascular phenotype Benign:1
Jun 08, 2015
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
10
DANN
Benign
0.83
PhyloP100
4.2
Mutation Taster
=99/1
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs36092484; hg19: chr9-130586657; API