rs104894497

Variant names:

• chr15-55228693-C-A
• rs104894497
• NM_183235.3:c.259G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-55228693-C-A
• chr15-55228693-C-G
• chr15-55228693-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_183235.3(RAB27A):​c.259G>T​(p.Ala87Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A87P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB27A NM_183235.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.81

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_183235.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-55228693-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5991.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}.
• 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.
• PP5: Variant 15-55228693-C-A is Pathogenic according to our data. Variant chr15-55228693-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2865253.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB27A	NM_183235.3	c.259G>T	p.Ala87Ser	missense_variant	Exon 5 of 7	ENST00000336787.6	NP_899058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787.6	c.259G>T	p.Ala87Ser	missense_variant	Exon 5 of 7	1	NM_183235.3	ENSP00000337761.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Griscelli syndrome type 2 Pathogenic:1

May 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 87 of the RAB27A protein (p.Ala87Ser). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala87 amino acid residue in RAB27A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16278825, 25544030, 26880764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAB27A protein function. This variant has not been reported in the literature in individuals affected with RAB27A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;D;D;T;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;.;.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-1.1	N;N;N;N;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Benign	0.092	T;T;T;T;.;.;T;.
Polyphen		0.90	P;P;P;P;.;.;.;.
Vest4		0.64
MutPred		0.79		Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);Gain of disorder (P = 0.0792);
MVP		0.49
MPC		0.14
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.62

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: rs104894497; hg19: chr15-55520891;