Genetic Variant RAB27A:c.*1931T>C (chr15-55203576-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_183235.3(RAB27A):c.*1931T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 146,360 control chromosomes in the GnomAD database, including 6,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6946 hom., cov: 26)

Exomes 𝑓: 0.0093 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAB27A
NM_183235.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0810

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BP6

Variant 15-55203576-A-G is Benign according to our data. Variant chr15-55203576-A-G is described in ClinVar as [Benign]. Clinvar id is 316612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB27A	NM_183235.3 link	c.*1931T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000336787.6	NP_899058.1	P51159-1A2RU94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB27A	ENST00000336787 link	c.*1931T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_183235.3	ENSP00000337761.1		P51159-1

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

39722

AN:

146300

Hom.:

6927

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.474

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.183

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.232

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00935

AC:

AN:

214

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

AN XY:

164

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:

0.0111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.272

AC:

39779

AN:

146360

Hom.:

6946

Cov.:

AF XY:

0.266

AC XY:

18918

AN XY:

70998

show subpopulations

Gnomad4 AFR

AF:

0.499

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.157

Gnomad4 EAS

AF:

0.122

Gnomad4 SAS

AF:

0.226

Gnomad4 FIN

AF:

0.172

Gnomad4 NFE

AF:

0.192

Gnomad4 OTH

AF:

0.231

Alfa

AF:

0.216

Hom.:

474

Bravo

AF:

0.277

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Griscelli syndrome type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.4

DANN

Benign

0.072

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