NM_183235.3:c.240-21A>G

Variant names:

• chr15-55228733-T-C
• rs368760836
• NM_183235.3:c.240-21A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_183235.3(RAB27A):​c.240-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,560,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: RAB27A NM_183235.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.152
• Publications: 0 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=-0.81).
• BP6: Variant 15-55228733-T-C is Benign according to our data. Variant chr15-55228733-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000208 (293/1408524) while in subpopulation MID AF = 0.00441 (25/5674). AF 95% confidence interval is 0.00306. There are 4 homozygotes in GnomAdExome4. There are 175 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.240-21A>G		intron	N/A	NP_899058.1
	RAB27A	NM_001438970.1		c.240-21A>G		intron	N/A	NP_001425899.1
	RAB27A	NM_001438972.1		c.240-21A>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.240-21A>G		intron	N/A	ENSP00000337761.1
	RAB27A	ENST00000396307.6	TSL:1	c.240-21A>G		intron	N/A	ENSP00000379601.2
	RAB27A	ENST00000564609.5	TSL:1	c.240-21A>G		intron	N/A	ENSP00000455012.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000348 AC: 87 AN: 250306 AF XY: 0.000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000208 AC: 293 AN: 1408524 Hom.: 4 Cov.: 25 AF XY: 0.000249 AC XY: 175 AN XY: 703860

African (AFR) AF: 0.000155 AC: 5 AN: 32258

American (AMR) AF: 0.000785 AC: 35 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.000503 AC: 13 AN: 25826

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39416

South Asian (SAS) AF: 0.00120 AC: 102 AN: 85214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00441 AC: 25 AN: 5674

European-Non Finnish (NFE) AF: 0.0000752 AC: 80 AN: 1063534

Other (OTH) AF: 0.000375 AC: 22 AN: 58650

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.000289 AC: 1 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	-0.81
CADD	Benign	0.18
DANN	Benign	0.56
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs368760836; hg19: chr15-55520931;