rs863223416
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000020.3(ACVRL1):c.406_409del(p.Gly136SerfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ACVRL1
NM_000020.3 frameshift
NM_000020.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.94
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-51913648-CTGGG-C is Pathogenic according to our data. Variant chr12-51913648-CTGGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212806.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.406_409del | p.Gly136SerfsTer28 | frameshift_variant | 4/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.406_409del | p.Gly136SerfsTer28 | frameshift_variant | 4/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152250
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000822 AC: 2AN: 243456Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132630
GnomAD3 exomes
AF:
AC:
2
AN:
243456
Hom.:
AF XY:
AC XY:
1
AN XY:
132630
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1454956Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724208
GnomAD4 exome
AF:
AC:
1
AN:
1454956
Hom.:
AF XY:
AC XY:
1
AN XY:
724208
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
GnomAD4 genome
?
AF:
AC:
1
AN:
152250
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74372
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely 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 | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Gly136Serfs*28) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is present in population databases (rs750662466, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 10694922, 15879500). This variant is also known as p.G136fs. ClinVar contains an entry for this variant (Variation ID: 212806). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 17, 2020 | The ACVRL1 c.406_409delGGTG; p.Gly136fs variant (rs863223416) is reported in the literature in an individual with HHT (Klaus 1998), and is reported in the ClinVar database (Variation ID: 212806). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Klaus DJ et al. Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online. Hum Mutat. 1998;12(2):137. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15879500, 10694922) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2021 | PP4, PM1, PVS1 - |
ACVRL1-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2023 | The ACVRL1 c.406_409delGGTG variant is predicted to result in a frameshift and premature protein termination (p.Gly136Serfs*28). This variant has been reported to be causative for hereditary hemorrhagic telangiectasia (HHT) (Klaus et al. 1997. PubMed ID: 10694922) This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-52307432-CTGGG-C). Frameshift variants in ACVRL1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The c.406_409delGGTG pathogenic mutation, located in coding exon 3 of the ACVRL1 gene, results from a deletion of 4 nucleotides at nucleotide positions 406 to 409, causing a translational frameshift with a predicted alternate stop codon (p.G136Sfs*28). In one study, this variant was seen in an individual with hereditary hemorrhagic telangiectasia (HHT) (Klaus DJ et al. Hum Mutat. 1998:12(2):137). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at