chr15-55223938-G-C

Position:

• chr15-55223938-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_183235.3(RAB27A):​c.418C>G​(p.Gln140Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,613,554 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: 0.00052 (1 hom.)
• Consequence: RAB27A NM_183235.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.88

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14190441).
• BP6: Variant 15-55223938-G-C is Benign according to our data. Variant chr15-55223938-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536462.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000518 (757/1461516) while in subpopulation MID AF= 0.00104 (6/5768). AF 95% confidence interval is 0.0006. There are 1 homozygotes in gnomad4_exome. There are 402 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB27A	NM_183235.3	c.418C>G	p.Gln140Glu	missense_variant	6/7	ENST00000336787.6	NP_899058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787.6	c.418C>G	p.Gln140Glu	missense_variant	6/7	1	NM_183235.3	ENSP00000337761.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251328 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135836

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000518 AC: 757 AN: 1461516 Hom.: 1 Cov.: 31 AF XY: 0.000553 AC XY: 402 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000640

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74258

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.00104

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Griscelli syndrome type 2 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The RAB27A p.Gln140Glu variant was not identified in the literature but was identified in dbSNP (ID: rs150463407) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 101 of 282708 chromosomes at a frequency of 0.0003573 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 83 of 129094 chromosomes (freq: 0.000643), Ashkenazi Jewish in 4 of 10366 chromosomes (freq: 0.000386), Other in 2 of 7218 chromosomes (freq: 0.000277), Latino in 9 of 35438 chromosomes (freq: 0.000254) and African in 3 of 24962 chromosomes (freq: 0.00012), but was not observed in the East Asian, European (Finnish), or South Asian populations. The p.Gln140 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.28
DEOGEN2	Benign	0.28	T;T;T;T;T;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.20	N;N;N;N;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;.;.
Polyphen		0.0080	B;B;B;B;.;.
Vest4		0.64
MVP		0.78
MPC		0.030
ClinPred		0.13	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.72

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: rs150463407; hg19: chr15-55516136;