Variant 15-55234785-TC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_183235.3(RAB27A):c.149del(p.Arg50LysfsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000994 in 1,609,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RAB27A
NM_183235.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.04

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-55234785-TC-T is Pathogenic according to our data. Variant chr15-55234785-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 504894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB27A	NM_183235.3 linkuse as main transcript	c.149del	p.Arg50LysfsTer35	frameshift_variant	3/7	ENST00000336787.6	NP_899058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787.6 linkuse as main transcript	c.149del	p.Arg50LysfsTer35	frameshift_variant	3/7	1	NM_183235.3	ENSP00000337761	P1	P51159-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250776

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1457494

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Griscelli syndrome type 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 13, 2024	This sequence change creates a premature translational stop signal (GRCh38; NM_183236.3:c.149del:p.Arg50LysfsTer35) in the RAB27A protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. ClinVar contains an entry for this variant (Variation ID: 504894). This variant is associated with the following publications: PubMed: 12148598, 10835631, 23160464, 16551969, 18350256, 19953648, 26684649 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Griscelli syndrome (PMID: 10835631, 12148598). ClinVar contains an entry for this variant (Variation ID: 504894). This variant is present in population databases (rs770601673, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg50Lysfs*35) in the RAB27A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB27A are known to be pathogenic (PMID: 10835631, 23160464). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 25, 2022	- -

Griscelli syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 23, 2016

The p.Arg50LysfsX35 variant in RAB27A has been reported in 4 individuals with Gr iscelli syndrome type 2 in the homozygous state (Menasche 2000). This variant ha s also been identified in 2/66,636 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg50LysfsX35 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 35 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Gri scelli syndrome type 2 in an autosomal recessive manner based upon case studies, low population frequency and functional prediction. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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