Genetic Variant RAB40A:p.Pro42Leu (chrX-103500632-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080879.3(RAB40A):c.125C>T(p.Pro42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00907 in 1,208,298 control chromosomes in the GnomAD database, including 34 homozygotes. There are 3,419 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 1 hom., 146 hem., cov: 22)

Exomes 𝑓: 0.0094 ( 33 hom. 3273 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010980219).

BS2

High Hemizygotes in GnomAd4 at 146 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40A	NM_080879.3 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 3 of 3	ENST00000304236.2	NP_543155.2	Q8WXH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB40A	ENST00000304236.2 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 3 of 3	2	NM_080879.3	ENSP00000305648.1	Q8WXH6
RAB40A	ENST00000372633.1 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 1 of 1	6		ENSP00000361716.1	Q8WXH6
ENSG00000234405	ENST00000658164.1 link	n.999+3019G>A		intron_variant	Intron 2 of 2
ENSG00000234405	ENST00000667819.1 link	n.302+3019G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00598

AC:

658

AN:

110046

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

146

AN XY:

32304

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00252

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00923

Gnomad OTH

AF:

0.00682

GnomAD3 exomes

AF:

0.00601

AC:

1103

AN:

183513

Hom.:

AF XY:

0.00580

AC XY:

394

AN XY:

67941

show subpopulations

Gnomad AFR exome

AF:

0.000836

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0000721

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00225

Gnomad NFE exome

AF:

0.00961

Gnomad OTH exome

AF:

0.00861

GnomAD4 exome

AF:

0.00938

AC:

10301

AN:

1098202

Hom.:

Cov.:

AF XY:

0.00900

AC XY:

3273

AN XY:

363594

show subpopulations

Gnomad4 AFR exome

AF:

0.000682

Gnomad4 AMR exome

AF:

0.00497

Gnomad4 ASJ exome

AF:

0.0117

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00247

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00772

GnomAD4 genome

AF:

0.00598

AC:

658

AN:

110096

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

146

AN XY:

32364

show subpopulations

Gnomad4 AFR

AF:

0.00129

Gnomad4 AMR

AF:

0.00708

Gnomad4 ASJ

AF:

0.0133

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00252

Gnomad4 NFE

AF:

0.00923

Gnomad4 OTH

AF:

0.00673

Alfa

AF:

0.00599

Hom.:

Bravo

AF:

0.00639

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.0120

AC:

ExAC

AF:

0.00593

AC:

720

EpiCase

AF:

0.00720

EpiControl

AF:

0.00937

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Vavilov Institute of General Genetics RAS, Laboratory of Evolutional Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.88

.;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.048

D;D

Polyphen

1.0

D;D

Vest4

0.21

MVP

0.94

MPC

1.9

ClinPred

0.075

GERP RS

-0.71

Varity_R

0.24

gMVP

0.75

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