rs182849552

Positions:

chr15-55205613-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_183235.3(RAB27A):c.560G>A(p.Arg187Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000163 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

RAB27A
NM_183235.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.95

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:

RAB27A (HGNC:):

RAB27A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0070313215).

BP6

Variant 15-55205613-C-T is Benign according to our data. Variant chr15-55205613-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235346.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152302) while in subpopulation EAS AF= 0.00521 (27/5178). AF 95% confidence interval is 0.00368. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB27A	NM_183235.3 linkuse as main transcript	c.560G>A	p.Arg187Gln	missense_variant	7/7	ENST00000336787.6	NP_899058.1	P51159-1A2RU94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787.6 linkuse as main transcript	c.560G>A	p.Arg187Gln	missense_variant	7/7	1	NM_183235.3	ENSP00000337761.1		P51159-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000525

AC:

132

AN:

251456

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00707

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000150

AC:

220

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00285

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.000282

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0103

Hom.:

816

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Griscelli syndrome type 2

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 22, 2021	RAB27A NM_004580.4 exon6 p.Arg187Gln (c.560G>A): This variant has been reported in the literature in the heterozygous state in at least two individuals affected by refractory hemophagocytic lymphohistiocytosis, with no second variant in RAB27A identified (Zhao 2019 PMID:31164711). This variant is also present in 0.6% (137/19954) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-55497811-C-T) and is present in ClinVar (Variation ID:235346). Computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 26, 2024

Variant summary: RAB27A c.560G>A (p.Arg187Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251456 control chromosomes (gnomAD). c.560G>A has been reported in the literature in individuals affected with Haemophagocytic lymphohistiocytosis or Menieres disease without strong evidence of causality (Zhao_2020, Guan_2021, Zou_2023). These reports do not provide unequivocal conclusions about association of the variant with Griscelli Syndrome Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31164711, 34170459, 37273692). ClinVar contains an entry for this variant (Variation ID: 235346). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RAB27A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

The RAB27A c.560G>A variant is predicted to result in the amino acid substitution p.Arg187Gln. This variant has been reported in the heterozygous state in two individuals with hemophagocytic lymphohistiocytosis and one individual with a chronic active EBV infection of T/NK-cell type (Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399; Table S1, Guan YQ et al. 2021. PubMed ID: 34170459). In both individuals with hemophagocytic lymphohistiocytosis, this variant was reported to be inherited, in one case from a parent who was noted to have impaired NK cytotoxicity function (Figure 2, Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55497811-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 02, 2015

- -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.096

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

.;T;.;.

M_CAP

Benign

0.0096

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.64

N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

0.77

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.34

MVP

0.37

MPC

0.018

ClinPred

0.067

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.51

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