rs182849552
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_183235.3(RAB27A):c.560G>A(p.Arg187Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000163 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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 Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000525 AC: 132AN: 251456Hom.: 0 AF XY: 0.000515 AC XY: 70AN XY: 135910
GnomAD4 exome AF: 0.000150 AC: 220AN: 1461844Hom.: 1 Cov.: 32 AF XY: 0.000151 AC XY: 110AN XY: 727230
GnomAD4 genome AF: 0.000282 AC: 43AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74468
ClinVar
Submissions by phenotype
Griscelli syndrome type 2 Uncertain:2Benign:2
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RAB27A NM_004580.4 exon6 p.Arg187Gln (c.560G>A): This variant has been reported in the literature in the heterozygous state in at least two individuals affected by refractory hemophagocytic lymphohistiocytosis, with no second variant in RAB27A identified (Zhao 2019 PMID:31164711). This variant is also present in 0.6% (137/19954) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-55497811-C-T) and is present in ClinVar (Variation ID:235346). Computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not specified Uncertain:1
Variant summary: RAB27A c.560G>A (p.Arg187Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251456 control chromosomes (gnomAD). c.560G>A has been reported in the literature in individuals affected with Haemophagocytic lymphohistiocytosis or Menieres disease without strong evidence of causality (Zhao_2020, Guan_2021, Zou_2023). These reports do not provide unequivocal conclusions about association of the variant with Griscelli Syndrome Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31164711, 34170459, 37273692). ClinVar contains an entry for this variant (Variation ID: 235346). Based on the evidence outlined above, the variant was classified as uncertain significance. -
RAB27A-related disorder Uncertain:1
The RAB27A c.560G>A variant is predicted to result in the amino acid substitution p.Arg187Gln. This variant has been reported in the heterozygous state in two individuals with hemophagocytic lymphohistiocytosis and one individual with a chronic active EBV infection of T/NK-cell type (Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399; Table S1, Guan YQ et al. 2021. PubMed ID: 34170459). In both individuals with hemophagocytic lymphohistiocytosis, this variant was reported to be inherited, in one case from a parent who was noted to have impaired NK cytotoxicity function (Figure 2, Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55497811-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
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Autoinflammatory syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at