rs200956636

chr15-55205623-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_183235.3(RAB27A):c.550C>T(p.Arg184Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0001 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

RAB27A
NM_183235.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.174 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-55205623-G-A is Pathogenic according to our data. Variant chr15-55205623-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 436458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB27A	NM_183235.3 linkuse as main transcript	c.550C>T	p.Arg184Ter	stop_gained	7/7	ENST00000336787.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB27A	ENST00000336787.6 linkuse as main transcript	c.550C>T	p.Arg184Ter	stop_gained	7/7	1	NM_183235.3	P1	P51159-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251432

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000960

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Griscelli syndrome type 2

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 25, 2018	The observed variant c.550C>T (p.Arg184Ter) has not been reported in 1000 Genomes database and has a minor allele frequency of 0.007% in the ExAC database. The in silico prediction of the given variant is damaging by MutationTaster2 and LRT. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This stop gained variant c.550C>T (p.Arg184Ter) has been reported in homozygous or in compound heterozygous state in individuals and families affected with Griscelli syndrome (Ariffin H et al), and has been shown to segregate with disease in two families (Meeths M et al). The c.550C>T variant is reported with the allele frequency of 0.006364% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This sequence change results in a premature translational stop signal in the RAB27A gene (p.Arg184*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acids of the RAB27A protein. The nucleotide change c.550C>T in RAB27A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This sequence change creates a premature translational stop signal (p.Arg184*) in the RAB27A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the RAB27A protein. This variant is present in population databases (rs200956636, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Griscelli syndrome (PMID: 10835631, 15475639, 18397837, 19030707, 19953648, 25071262, 25500851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 436458). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2018

- -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.85

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over