dbSNP rs566144766: RAB27A:c.*1863C>T (chr15-55203644-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_183235.3(RAB27A):c.*1863C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 145,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAB27A
NM_183235.3 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Griscelli syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

RAB27A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00404 (590/145988) while in subpopulation NFE AF = 0.00642 (430/66966). AF 95% confidence interval is 0.00592. There are 1 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAB27A	NM_183235.3	MANE Select	c.*1863C>T	3_prime_UTR	Exon 7 of 7	NP_899058.1	P51159-1
RAB27A	NM_001438970.1		c.*1863C>T	3_prime_UTR	Exon 8 of 8	NP_001425899.1
RAB27A	NM_001438972.1		c.*1863C>T	3_prime_UTR	Exon 7 of 7	NP_001425901.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAB27A	ENST00000336787.6	TSL:1 MANE Select	c.*1863C>T	3_prime_UTR	Exon 7 of 7	ENSP00000337761.1	P51159-1
RAB27A	ENST00000396307.6	TSL:1	c.*1863C>T	3_prime_UTR	Exon 6 of 6	ENSP00000379601.2	P51159-1
RAB27A	ENST00000697642.1		c.*1863C>T	3_prime_UTR	Exon 6 of 6	ENSP00000513368.1	P51159-1

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

590

AN:

145898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00136

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00329

Gnomad ASJ

AF:

0.00759

Gnomad EAS

AF:

0.000406

Gnomad SAS

AF:

0.00367

Gnomad FIN

AF:

0.000225

Gnomad MID

AF:

0.00667

Gnomad NFE

AF:

0.00642

Gnomad OTH

AF:

0.00455

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.00404

AC:

590

AN:

145988

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

295

AN XY:

70582

show subpopulations

African (AFR)

AF:

0.00136

AC:

AN:

39722

American (AMR)

AF:

0.00329

AC:

AN:

14290

Ashkenazi Jewish (ASJ)

AF:

0.00759

AC:

AN:

3426

East Asian (EAS)

AF:

0.000407

AC:

AN:

4910

South Asian (SAS)

AF:

0.00368

AC:

AN:

4614

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

8888

Middle Eastern (MID)

AF:

0.00725

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00642

AC:

430

AN:

66966

Other (OTH)

AF:

0.00452

AC:

AN:

1992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Griscelli syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.3

(source)

DANN

Benign

0.76

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over