X-103500501-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_080879.3(RAB40A):​c.256G>A​(p.Gly86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,208,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G86V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000047 ( 0 hom. 16 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

2
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.42230913).
BS2
High Hemizygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB40ANM_080879.3 linkc.256G>A p.Gly86Ser missense_variant Exon 3 of 3 ENST00000304236.2 NP_543155.2 Q8WXH6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAB40AENST00000304236.2 linkc.256G>A p.Gly86Ser missense_variant Exon 3 of 3 2 NM_080879.3 ENSP00000305648.1 Q8WXH6

Frequencies

GnomAD3 genomes
AF:
0.0000271
AC:
3
AN:
110800
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
32986
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:
0.0000570
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000437
AC:
8
AN:
182949
Hom.:
0
AF XY:
0.0000297
AC XY:
2
AN XY:
67453
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000109
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000613
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000474
AC:
52
AN:
1098066
Hom.:
0
Cov.:
33
AF XY:
0.0000440
AC XY:
16
AN XY:
363444
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000852
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000558
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000271
AC:
3
AN:
110800
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
32986
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000570
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000299
AC:
2
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.256G>A (p.G86S) alteration is located in exon 3 (coding exon 1) of the RAB40A gene. This alteration results from a G to A substitution at nucleotide position 256, causing the glycine (G) at amino acid position 86 to be replaced by a serine (S). 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
0.19
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;T
FATHMM_MKL
Benign
0.36
N
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.42
T;T
MetaSVM
Uncertain
-0.066
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Uncertain
0.53
Sift
Uncertain
0.0090
D;D
Sift4G
Benign
0.063
T;T
Polyphen
1.0
D;D
Vest4
0.26
MVP
0.99
MPC
1.3
ClinPred
0.89
D
GERP RS
0.23
Varity_R
0.63
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs373230359; hg19: chrX-102755429; API