rs104894497

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_183235.3(RAB27A):c.259G>C(p.Ala87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,508 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

RAB27A
NM_183235.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.81

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 15-55228693-C-G is Pathogenic according to our data. 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, Pathogenic=1, Likely_pathogenic=1}. Variant chr15-55228693-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB27A	NM_183235.3 linkuse as main transcript	c.259G>C	p.Ala87Pro	missense_variant	5/7	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.259G>C	p.Ala87Pro	missense_variant	5/7	1	NM_183235.3	ENSP00000337761.1		P51159-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251174

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461304

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000112

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	Published functional studies demonstrate a damaging effect with decreased binding to Munc13-4 and delayed granzyme B polarization towards the immunologic synapse (Zhang et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16278825, 26597256, 26880764, 18350256, 20370853, 25544030, 32638196) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Griscelli syndrome type 2

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 87 of the RAB27A protein (p.Ala87Pro). This variant is present in population databases (rs104894497, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis and Griscelli syndrome (PMID: 16278825, 25544030). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5991). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAB27A function (PMID: 16278825, 26880764). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2014

The Ala87Pro variant in RAB27A has been identified in one individual with familial hemophagocytic lymphohistiocytosis who also carried a loss-of-function RAB27A variant in trans (Stadt 2006). Functional studies indicate this variant leads to the disruption of RAB27A binding with UNC13D and in decreased cytolytic activity and inhibited granulation (Cron and Zhang 2013, Abstract). In summary, although this data supports that this variant may be pathogenic, additional studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;D;D;D;.;.;D

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;D;.;.;D;D;D;D

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.022

MutationAssessor

Benign

1.2

L;L;L;L;.;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;.;.;D;.

Polyphen

1.0

D;D;D;D;.;.;.;.

Vest4

0.94

MVP

0.69

MPC

0.16

ClinPred

0.67

GERP RS

5.9

Varity_R

0.97

gMVP

0.90

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