rs1060503235
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_SupportingPM2_SupportingPVS1
This summary comes from the ClinGen Evidence Repository: The NM_000020.3: c.1217G>A (p.Trp406Ter) variant in ACVRL1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8 (out of 10) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic 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: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614169/MONDO:0010880/135
Frequency
Consequence
NM_000020.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.1217G>A | p.Trp406Ter | stop_gained | 8/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.1217G>A | p.Trp406Ter | stop_gained | 8/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 26, 2016 | This sequence change creates a premature translational stop signal at codon 406 (p.Trp406*) of the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen | Mar 15, 2024 | The NM_000020.3: c.1217G>A (p.Trp406Ter) variant in ACVRL1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8 (out of 10) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic 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: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at