Genetic Variant NM_016530.3:c.608G>A (chr15-63263603-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_016530.3(RAB8B):c.608G>A(p.Arg203His) variant causes a missense change. The variant allele was found at a frequency of 0.0000802 in 1,608,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 1 hom. )

Consequence

RAB8B
NM_016530.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

Publications

0 publications found

Variant links:

Genes affected

RAB8B (HGNC:30273): (RAB8B, member RAS oncogene family) RAB proteins, like RAB8B, are low molecular mass monomeric GTPases that localize on the cytoplasmic surfaces of distinct membrane-bound organelles. RAB proteins function in intracellular vesicle transport by aiding in the docking and/or fusion of vesicles with their target membranes (summary by Chen et al., 1997 [PubMed 9030196]).[supplied by OMIM, Nov 2010]

RAB8B 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 (MetaRNN=0.34842092).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB8B	NM_016530.3 link	c.608G>A	p.Arg203His	missense_variant	Exon 8 of 8	ENST00000321437.9	NP_057614.1	Q92930
RAB8B	XM_017022312.1 link	c.365G>A	p.Arg122His	missense_variant	Exon 9 of 9		XP_016877801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB8B	ENST00000321437.9 link	c.608G>A	p.Arg203His	missense_variant	Exon 8 of 8	1	NM_016530.3	ENSP00000312734.4	Q92930
RAB8B	ENST00000558119.5 link	n.*388G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000453679.1	H0YMN7
RAB8B	ENST00000558119.5 link	n.*388G>A		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000453679.1	H0YMN7
RAB8B	ENST00000559927.1 link	n.*593G>A		downstream_gene_variant		5		ENSP00000453111.1	H0YL94

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251372

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000803

AC:

117

AN:

1456248

Hom.:

Cov.:

AF XY:

0.0000731

AC XY:

AN XY:

724788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.0000671

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000697

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000940

AC:

104

AN:

1106924

Other (OTH)

AF:

0.0000664

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.608G>A (p.R203H) alteration is located in exon 8 (coding exon 8) of the RAB8B gene. This alteration results from a G to A substitution at nucleotide position 608, causing the arginine (R) at amino acid position 203 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.028

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.58

MutationAssessor

Benign

2.0

PhyloP100

3.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.022

Polyphen

0.94

Vest4

0.37

MVP

0.85

MPC

1.9

ClinPred

0.21

GERP RS

5.8

Varity_R

0.18

gMVP

0.59

Mutation Taster

=82/18

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_016530.3:c.608G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over