Genetic Variant NM_016370.4:c.265G>A (chrX-103825520-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016370.4(RAB9B):c.265G>A(p.Val89Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000281 in 1,209,958 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V89V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 0 hom. 8 hem. )

Consequence

RAB9B
NM_016370.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

Publications

1 publications found

Variant links:

Genes affected

RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]

RAB9B links:

ENSG00000288597 (HGNC:):

ENSG00000288597 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2493878).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016370.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB9B	NM_016370.4	MANE Select	c.265G>A	p.Val89Met	missense	Exon 3 of 3	NP_057454.1	Q9NP90
RAB9B	NR_146558.2		n.198+6540G>A		intron	N/A
RAB9B	NR_146560.2		n.198+6540G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB9B	ENST00000243298.3	TSL:1 MANE Select	c.265G>A	p.Val89Met	missense	Exon 3 of 3	ENSP00000243298.2	Q9NP90
RAB9B	ENST00000873736.1		c.265G>A	p.Val89Met	missense	Exon 2 of 2	ENSP00000543795.1
RAB9B	ENST00000963274.1		c.265G>A	p.Val89Met	missense	Exon 2 of 2	ENSP00000633333.1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111693

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00140

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

182976

AF XY:

0.0000888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1098210

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000828

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842127

Other (OTH)

AF:

0.0000434

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111748

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33918

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30764

American (AMR)

AF:

0.00

AC:

AN:

10510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00140

AC:

AN:

3568

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53139

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

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:

0.0000341

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000988

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.25

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.4

PhyloP100

6.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.77

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

0.99

Vest4

0.58

MutPred

0.78

Loss of catalytic residue at V89 (P = 0.0243)

MVP

0.98

MPC

1.7

ClinPred

0.19

GERP RS

5.8

Varity_R

0.73

gMVP

0.88

Mutation Taster

=64/36

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over