rs878853415
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000020.3(ACVRL1):βc.696_698delβ(p.Ser233del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
ACVRL1
NM_000020.3 inframe_deletion
NM_000020.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
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 13 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000020.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000020.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 12-51914505-TCTC-T is Pathogenic according to our data. Variant chr12-51914505-TCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 236552.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.696_698del | p.Ser233del | inframe_deletion | 6/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.696_698del | p.Ser233del | inframe_deletion | 6/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This variant, c.696_698del, results in the deletion of 1 amino acid(s) of the ACVRL1 protein (p.Ser233del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225, 15024723, 16752392, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236552). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 28, 2020 | PP1_Strong, PS4, PP4, PM4, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2022 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10767348, 16752392, 21158752, 9245985, 15266205, 8640225, 15024723) - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 16, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2022 | The c.696_698delCTC pathogenic mutation (also known as p.S233del) is located in coding exon 5 of the ACVRL1 gene. This pathogenic mutation results from an in-frame CTC deletion at nucleotide positions 696 to 698. This results in the in-frame deletion of a serine at codon 233. This pathogenic mutation segregated with disease in a large family affected with hereditary hemorrhagic telangiectasia (HHT); however, there were a few unaffected carriers, which was attributed to incomplete penetrance (Johnson DW et al. Nat. Genet., 1996 Jun;13:189-95). This pathogenic mutation was also observed in an individual that presented with epistaxis, telangiectasias, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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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