chr15-55234785-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_183235.3(RAB27A):βc.149delGβ(p.Arg50LysfsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000994 in 1,609,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_183235.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250776Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135532
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1457494Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7AN XY: 725334
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
Griscelli syndrome type 2 Pathogenic:3
This sequence change creates a premature translational stop signal (GRCh38; NM_183236.3:c.149del:p.Arg50LysfsTer35) in the RAB27A protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. ClinVar contains an entry for this variant (Variation ID: 504894). This variant is associated with the following publications: PubMed: 12148598, 10835631, 23160464, 16551969, 18350256, 19953648, 26684649 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined. -
This sequence change creates a premature translational stop signal (p.Arg50Lysfs*35) in the RAB27A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB27A are known to be pathogenic (PMID: 10835631, 23160464). This variant is present in population databases (rs770601673, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Griscelli syndrome (PMID: 10835631, 12148598). ClinVar contains an entry for this variant (Variation ID: 504894). For these reasons, this variant has been classified as Pathogenic. -
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Griscelli syndrome Pathogenic:1
The p.Arg50LysfsX35 variant in RAB27A has been reported in 4 individuals with Gr iscelli syndrome type 2 in the homozygous state (Menasche 2000). This variant ha s also been identified in 2/66,636 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg50LysfsX35 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 35 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Gri scelli syndrome type 2 in an autosomal recessive manner based upon case studies, low population frequency and functional prediction. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at