15-55205613-C-G

Variant names:

• chr15-55205613-C-G
• rs182849552
• NM_183235.3:c.560G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_183235.3(RAB27A):​c.560G>C​(p.Arg187Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB27A NM_183235.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.51469 (below the threshold of 3.09). Trascript score misZ: 0.058062 (below the threshold of 3.09). GenCC associations: The gene is linked to Griscelli syndrome type 2.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB27A	NM_183235.3	MANE Select	c.560G>C	p.Arg187Pro	missense	Exon 7 of 7	NP_899058.1	P51159-1
	RAB27A	NM_001438970.1		c.560G>C	p.Arg187Pro	missense	Exon 8 of 8	NP_001425899.1
	RAB27A	NM_001438972.1		c.560G>C	p.Arg187Pro	missense	Exon 7 of 7	NP_001425901.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB27A	ENST00000336787.6	TSL:1 MANE Select	c.560G>C	p.Arg187Pro	missense	Exon 7 of 7	ENSP00000337761.1	P51159-1
	RAB27A	ENST00000396307.6	TSL:1	c.560G>C	p.Arg187Pro	missense	Exon 6 of 6	ENSP00000379601.2	P51159-1
	RAB27A	ENST00000564609.5	TSL:1	c.560G>C	p.Arg187Pro	missense	Exon 7 of 7	ENSP00000455012.1	P51159-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.040	D
Polyphen		0.67	P
Vest4		0.56
MutPred		0.44		Loss of MoRF binding (P = 0.0019)
MVP		0.52
MPC		0.071
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.81
Mutation Taster		=22/78	disease causing

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: rs182849552; hg19: chr15-55497811;