15-55203576-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_183235.3(RAB27A):c.*1931T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 146,360 control chromosomes in the GnomAD database, including 6,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (6946 hom., cov: 26)
  • Exomes 𝑓: 0.0093 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAB27A NM_183235.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0810

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 15-55203576-A-G is Benign according to our data. Variant chr15-55203576-A-G is described in ClinVar as [Benign]. Clinvar id is 316612.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB27A	NM_183235.3	c.*1931T>C		3_prime_UTR_variant	7/7	ENST00000336787.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB27A	ENST00000336787.6	c.*1931T>C		3_prime_UTR_variant	7/7	1	NM_183235.3	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 39722 AN: 146300 Hom.: 6927 Cov.: 26

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.232

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00935 AC: 2 AN: 214 Hom.: 0 Cov.: 0 AF XY: 0.00610 AC XY: 1 AN XY: 164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.272 AC: 39779 AN: 146360 Hom.: 6946 Cov.: 26 AF XY: 0.266 AC XY: 18918 AN XY: 70998

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.231

Alfa AF: 0.216 Hom.: 474

Bravo AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Griscelli syndrome type 2 Benign:1

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	-1.0
Cadd	Benign	1.4
Dann	Benign	0.072

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: rs6493770; hg19: chr15-55495774;