Genetic Variant RAB40A:p.Pro42Gln (chrX-103500632-G-T) – 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_080879.3(RAB40A):c.125C>A(p.Pro42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,208,249 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.50

Publications

14 publications found

Variant links:

Genes affected

RAB40A (HGNC:18283): (RAB40A, member RAS oncogene family) This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box. [provided by RefSeq, Apr 2010]

RAB40A links:

LL0XNC01-250H12.3 (HGNC:):

LL0XNC01-250H12.3 links:

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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=0.39620858).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080879.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB40A	NM_080879.3	MANE Select	c.125C>A	p.Pro42Gln	missense	Exon 3 of 3	NP_543155.2	Q8WXH6
LL0XNC01-250H12.3	NR_188433.1		n.2302G>T		non_coding_transcript_exon	Exon 9 of 9
LL0XNC01-250H12.3	NR_188435.1		n.2229G>T		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB40A	ENST00000304236.2	TSL:2 MANE Select	c.125C>A	p.Pro42Gln	missense	Exon 3 of 3	ENSP00000305648.1	Q8WXH6
RAB40A	ENST00000372633.1	TSL:6	c.125C>A	p.Pro42Gln	missense	Exon 1 of 1	ENSP00000361716.1	Q8WXH6
RAB40A	ENST00000905301.1		c.125C>A	p.Pro42Gln	missense	Exon 4 of 4	ENSP00000575360.1

Frequencies

GnomAD3 genomes

AF:

0.00000909

AC:

AN:

110047

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098202

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

842101

Other (OTH)

AF:

0.0000217

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00000909

AC:

AN:

110047

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

32305

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30177

American (AMR)

AF:

0.00

AC:

AN:

10445

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3507

South Asian (SAS)

AF:

0.00

AC:

AN:

2413

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5953

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52539

Other (OTH)

AF:

0.00

AC:

AN:

1467

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.86

M_CAP

Benign

0.0065

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.26

PhyloP100

3.5

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.27

MutPred

0.33

Gain of sheet (P = 0.0344)

MVP

0.94

MPC

1.8

ClinPred

0.98

GERP RS

-0.71

Varity_R

0.30

gMVP

0.66

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over