rs369766351
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_001114753.3(ENG):c.1686+6T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 1 hom. )
Consequence
ENG
NM_001114753.3 splice_donor_region, intron
NM_001114753.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001308
2
Clinical Significance
Conservation
PhyloP100: 0.325
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 -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 9-127818114-A-C is Benign according to our data. Variant chr9-127818114-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 407130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127818114-A-C is described in Lovd as [Likely_benign]. Variant chr9-127818114-A-C is described in Lovd as [Benign].
BS2
?
High AC in GnomAd at 27 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.1686+6T>G | splice_donor_region_variant, intron_variant | ENST00000373203.9 | |||
LOC102723566 | NR_136302.1 | n.1378-197A>C | intron_variant, non_coding_transcript_variant | ||||
ENG | NM_000118.4 | c.1686+6T>G | splice_donor_region_variant, intron_variant | ||||
ENG | NM_001278138.2 | c.1140+6T>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.1686+6T>G | splice_donor_region_variant, intron_variant | 1 | NM_001114753.3 | P2 | |||
ENST00000439298.5 | n.1378-197A>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000200 AC: 50AN: 250564Hom.: 1 AF XY: 0.000207 AC XY: 28AN XY: 135514
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GnomAD4 exome AF: 0.000377 AC: 551AN: 1461730Hom.: 1 Cov.: 31 AF XY: 0.000362 AC XY: 263AN XY: 727182
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GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74324
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ClinVar
Significance: Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ENG: BP4 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2018 | 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. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pulmonary arterial hypertension Benign:1
Benign, no assertion criteria provided | clinical testing | John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine | Sep 26, 2022 | - - |
Telangiectasia, hereditary hemorrhagic, type 1 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Hereditary hemorrhagic telangiectasia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at