rs1060503237
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000020.3(ACVRL1):c.1378-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
ACVRL1
NM_000020.3 splice_acceptor
NM_000020.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.89
Genes affected
ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 1, new splice context is: cctctctcccaacccccaAGtcc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 12-51920758-G-A is Pathogenic according to our data. Variant chr12-51920758-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.1378-1G>A | splice_acceptor_variant | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.1378-1G>A | splice_acceptor_variant | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2016 | This sequence change affects an acceptor splice site in intron 9. It is expected to disrupt mRNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACVRL1-related disease. This variant is expected to result in the skipping of the last exon of ACVRL1 mRNA. Exon 10 codes for the last 28 residues of the ACVRL1 kinase domain and missense variants located in this exon have been shown to have a deleterious effect on protein function and stability (PMID: 11484689, 20501893, 23124896). For these reasons, this variant has been classified as Likely Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2022 | The c.1378-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 9 of the ACVRL1 gene. This alteration occurs at the 3' terminus of the ACVRL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 8.5% of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at