chr15-55228576-T-C

Variant names:

• chr15-55228576-T-C
• rs74015516
• NM_183235.3:c.343+33A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_183235.3(RAB27A):​c.343+33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00909 in 1,460,820 control chromosomes in the GnomAD database, including 1,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (583 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (495 hom.)
• Consequence: RAB27A NM_183235.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.669
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Griscelli syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-55228576-T-C is Benign according to our data. Variant chr15-55228576-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB27A	NM_183235.3	MANE Select	c.343+33A>G		intron	N/A	NP_899058.1
	RAB27A	NM_001438970.1		c.343+33A>G		intron	N/A	NP_001425899.1
	RAB27A	NM_001438972.1		c.343+33A>G		intron	N/A	NP_001425901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB27A	ENST00000336787.6	TSL:1 MANE Select	c.343+33A>G		intron	N/A	ENSP00000337761.1
	RAB27A	ENST00000396307.6	TSL:1	c.343+33A>G		intron	N/A	ENSP00000379601.2
	RAB27A	ENST00000564609.5	TSL:1	c.343+33A>G		intron	N/A	ENSP00000455012.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7033 AN: 152176 Hom.: 579 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0115 AC: 2898 AN: 250976 AF XY: 0.00819

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.00634

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00476 AC: 6223 AN: 1308526 Hom.: 495 Cov.: 21 AF XY: 0.00406 AC XY: 2678 AN XY: 659062

African (AFR) AF: 0.171 AC: 5182 AN: 30252

American (AMR) AF: 0.00708 AC: 315 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.000325 AC: 27 AN: 83110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00346 AC: 19 AN: 5486

European-Non Finnish (NFE) AF: 0.0000967 AC: 94 AN: 972162

Other (OTH) AF: 0.0106 AC: 586 AN: 55504

GnomAD4 genome AF: 0.0464 AC: 7063 AN: 152294 Hom.: 583 Cov.: 32 AF XY: 0.0457 AC XY: 3401 AN XY: 74462

African (AFR) AF: 0.163 AC: 6772 AN: 41538

American (AMR) AF: 0.0129 AC: 197 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68040

Other (OTH) AF: 0.0336 AC: 71 AN: 2110

Alfa AF: 0.0224 Hom.: 69

Bravo AF: 0.0524

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.51
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74015516; hg19: chr15-55520774;