rs41358947
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001114753.3(ENG):āc.1794T>Cā(p.Gly598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,610,468 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.014 ( 44 hom., cov: 33)
Exomes š: 0.0048 ( 110 hom. )
Consequence
ENG
NM_001114753.3 synonymous
NM_001114753.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.01
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
?
Variant 9-127816001-A-G is Benign according to our data. Variant chr9-127816001-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 213203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127816001-A-G is described in Lovd as [Benign]. Variant chr9-127816001-A-G is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.01 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2200/152302) while in subpopulation AFR AF= 0.0417 (1733/41554). AF 95% confidence interval is 0.0401. There are 44 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 2200 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.1794T>C | p.Gly598= | synonymous_variant | 14/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.1794T>C | p.Gly598= | synonymous_variant | 14/14 | ||
ENG | NM_001278138.2 | c.1248T>C | p.Gly416= | synonymous_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.1794T>C | p.Gly598= | synonymous_variant | 14/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.1794T>C | p.Gly598= | synonymous_variant | 14/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.1248T>C | p.Gly416= | synonymous_variant | 14/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0145 AC: 2200AN: 152184Hom.: 44 Cov.: 33
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GnomAD3 exomes AF: 0.00832 AC: 2019AN: 242772Hom.: 35 AF XY: 0.00885 AC XY: 1166AN XY: 131712
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GnomAD4 exome AF: 0.00485 AC: 7066AN: 1458166Hom.: 110 Cov.: 31 AF XY: 0.00562 AC XY: 4072AN XY: 725040
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GnomAD4 genome ? AF: 0.0144 AC: 2200AN: 152302Hom.: 44 Cov.: 33 AF XY: 0.0146 AC XY: 1084AN XY: 74488
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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
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2014 | 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, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 21, 2013 | Gly598Gly in exon 14A of ENG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 4.0% (178/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs41358947). - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Telangiectasia, hereditary hemorrhagic, type 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Hereditary hemorrhagic telangiectasia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2017 | 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at