12-51913648-CTGGG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000020.3(ACVRL1):c.406_409delGGTG(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
Consequence
NM_000020.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.406_409delGGTG | p.Gly136SerfsTer28 | frameshift_variant | Exon 4 of 10 | ENST00000388922.9 | NP_000011.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000822 AC: 2AN: 243456Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132630
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1454956Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724208
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2
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. PMID: 10694922 -
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. -
not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 15879500, 10694922) -
PP4, PM1, PVS1 -
ACVRL1-related disorder Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at