rs1050931

Positions:

• chr15-55205493-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_183235.3(RAB27A):​c.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,611,066 control chromosomes in the GnomAD database, including 38,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7077 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31137 hom.)
• Consequence: RAB27A NM_183235.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.101

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]

RAB27A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-55205493-G-A is Benign according to our data. Variant chr15-55205493-G-A is described in ClinVar as [Benign]. Clinvar id is 259442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB27A	NM_183235.3	c.*14C>T		3_prime_UTR_variant	7/7	ENST00000336787.6	NP_899058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787	c.*14C>T		3_prime_UTR_variant	7/7	1	NM_183235.3	ENSP00000337761.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40670 AN: 151952 Hom.: 7059 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.193 AC: 48500 AN: 251464 Hom.: 5744 AF XY: 0.193 AC XY: 26208 AN XY: 135904

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.199 AC: 290126 AN: 1458996 Hom.: 31137 Cov.: 32 AF XY: 0.199 AC XY: 144245 AN XY: 725956

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0987

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.268 AC: 40728 AN: 152070 Hom.: 7077 Cov.: 32 AF XY: 0.262 AC XY: 19450 AN XY: 74328

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.226

Alfa AF: 0.215 Hom.: 1224

Bravo AF: 0.277

Asia WGS AF: 0.220 AC: 765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Griscelli syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.4
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1050931; hg19: chr15-55497691; COSMIC: COSV61015156; COSMIC: COSV61015156;