rs182849552

chr15-55205613-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 BP4_Strong BP6 BS1

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: RAB27A NM_183235.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 4.95

Genes affected

RAB27A (HGNC:9766): (RAB27A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a chain Ras-related protein Rab-27A (size 219) in uniprot entity RB27A_HUMAN there are 23 pathogenic changes around while only 8 benign (74%) in NM_183235.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070313215).
• BP6: Variant 15-55205613-C-T is Benign according to our data. Variant chr15-55205613-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235346.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152302) while in subpopulation EAS AF= 0.00521 (27/5178). AF 95% confidence interval is 0.00368. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB27A	NM_183235.3	c.560G>A	p.Arg187Gln	missense_variant	7/7	ENST00000336787.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB27A	ENST00000336787.6	c.560G>A	p.Arg187Gln	missense_variant	7/7	1	NM_183235.3	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000525 AC: 132 AN: 251456 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00707

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000150 AC: 220 AN: 1461844 Hom.: 1 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00285

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0103 Hom.: 816

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Griscelli syndrome type 2 Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 22, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

RAB27A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 02, 2015

- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.64	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.77	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.34
MVP		0.37
MPC		0.018
ClinPred		0.067	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs182849552; hg19: chr15-55497811; COSMIC: COSV61016145; COSMIC: COSV61016145;