rs142803546

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000373203.9(ENG):​c.1095C>T​(p.Asp365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,613,980 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00050 ( 3 hom. )

Consequence

ENG
ENST00000373203.9 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.72
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 9-127824343-G-A is Benign according to our data. Variant chr9-127824343-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 365089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127824343-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.72 with no splicing effect.
BS2
High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ENGNM_001114753.3 linkuse as main transcriptc.1095C>T p.Asp365= synonymous_variant 8/15 ENST00000373203.9 NP_001108225.1
ENGNM_000118.4 linkuse as main transcriptc.1095C>T p.Asp365= synonymous_variant 8/14 NP_000109.1
ENGNM_001278138.2 linkuse as main transcriptc.549C>T p.Asp183= synonymous_variant 8/15 NP_001265067.1
ENGNM_001406715.1 linkuse as main transcriptc.1095C>T p.Asp365= synonymous_variant 8/8 NP_001393644.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ENGENST00000373203.9 linkuse as main transcriptc.1095C>T p.Asp365= synonymous_variant 8/151 NM_001114753.3 ENSP00000362299 P2P17813-1
ENGENST00000344849.4 linkuse as main transcriptc.1095C>T p.Asp365= synonymous_variant 8/141 ENSP00000341917 A2P17813-2
ENGENST00000480266.6 linkuse as main transcriptc.549C>T p.Asp183= synonymous_variant 8/152 ENSP00000479015
ENGENST00000486329.1 linkuse as main transcriptn.63C>T non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
151988
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.000961
GnomAD3 exomes
AF:
0.000354
AC:
89
AN:
251474
Hom.:
2
AF XY:
0.000419
AC XY:
57
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000520
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000425
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000466
Gnomad OTH exome
AF:
0.000814
GnomAD4 exome
AF:
0.000500
AC:
731
AN:
1461874
Hom.:
3
Cov.:
32
AF XY:
0.000514
AC XY:
374
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000336
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000593
Gnomad4 OTH exome
AF:
0.000281
GnomAD4 genome
AF:
0.000355
AC:
54
AN:
152106
Hom.:
0
Cov.:
30
AF XY:
0.000377
AC XY:
28
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000964
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.000951
Alfa
AF:
0.000179
Hom.:
0
Bravo
AF:
0.000366
EpiCase
AF:
0.000654
EpiControl
AF:
0.000415

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
ENG-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 09, 2020This 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). -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 13, 2017This 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. -
Hereditary hemorrhagic telangiectasia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 16, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.21
DANN
Benign
0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142803546; hg19: chr9-130586622; COSMIC: COSV100785214; COSMIC: COSV100785214; API