rs540520068

chr15-55230473-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_183235.3(RAB27A):c.167G>A(p.Ser56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,590 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S56S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (7 hom.)
• Consequence: RAB27A NM_183235.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.00

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 -18 ACMG points.

• PM1: In a chain Ras-related protein Rab-27A (size 219) in uniprot entity RB27A_HUMAN there are 23 pathogenic changes around while only 8 benign (74%) in NM_183235.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.005645305).
• BP6: Variant 15-55230473-C-T is Benign according to our data. Variant chr15-55230473-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 316650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000125 (19/152302) while in subpopulation SAS AF= 0.00393 (19/4832). AF 95% confidence interval is 0.00257. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB27A	NM_183235.3	c.167G>A	p.Ser56Asn	missense_variant	4/7	ENST00000336787.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB27A	ENST00000336787.6	c.167G>A	p.Ser56Asn	missense_variant	4/7	1	NM_183235.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000693 AC: 174 AN: 250904 Hom.: 3 AF XY: 0.000870 AC XY: 118 AN XY: 135604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000348 AC: 509 AN: 1461288 Hom.: 7 Cov.: 31 AF XY: 0.000481 AC XY: 350 AN XY: 726980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00529

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Griscelli syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	9.0
Dann	Benign	0.85
DEOGEN2	Benign	0.32	T;T;T;T;T;.;.;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N;N;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.15	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.87	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;.;.;T;.;.
Polyphen		0.0	B;B;B;B;.;.;.;.;.
Vest4		0.044
MutPred		0.36		Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);Loss of glycosylation at S56 (P = 0.0225);
MVP		0.25
MPC		0.018
ClinPred		0.028	T
GERP RS		3.5
Varity_R		0.047
gMVP		0.46

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: rs540520068; hg19: chr15-55522671;