rs104894497
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_183235.3(RAB27A):c.259G>C(p.Ala87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_183235.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251174Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135752
GnomAD4 exome AF: 0.000178 AC: 260AN: 1461304Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 127AN XY: 726998
GnomAD4 genome AF: 0.000112 AC: 17AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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Published functional studies demonstrate a damaging effect with decreased binding to Munc13-4 and delayed granzyme B polarization towards the immunologic synapse (Zhang et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16278825, 26597256, 26880764, 18350256, 20370853, 25544030, 32638196) -
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Griscelli syndrome type 2 Pathogenic:3
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 87 of the RAB27A protein (p.Ala87Pro). This variant is present in population databases (rs104894497, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis and Griscelli syndrome (PMID: 16278825, 25544030). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAB27A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAB27A function (PMID: 16278825, 26880764). For these reasons, this variant has been classified as Pathogenic. -
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not specified Uncertain:1
The Ala87Pro variant in RAB27A has been identified in one individual with familial hemophagocytic lymphohistiocytosis who also carried a loss-of-function RAB27A variant in trans (Stadt 2006). Functional studies indicate this variant leads to the disruption of RAB27A binding with UNC13D and in decreased cytolytic activity and inhibited granulation (Cron and Zhang 2013, Abstract). In summary, although this data supports that this variant may be pathogenic, additional studies are needed to fully assess its clinical significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at