X-103500110-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_080879.3(RAB40A):​c.647G>T​(p.Ser216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,209,585 control chromosomes in the GnomAD database, including 1 homozygotes. There are 356 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 9 hem., cov: 23)
Exomes 𝑓: 0.00060 ( 1 hom. 347 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

17

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.23
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 Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05337599).
BP6
Variant X-103500110-C-A is Benign according to our data. Variant chrX-103500110-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2332633.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-103500110-C-A is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB40ANM_080879.3 linkc.647G>T p.Ser216Ile 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.647G>T p.Ser216Ile missense_variant Exon 3 of 3 2 NM_080879.3 ENSP00000305648.1 Q8WXH6

Frequencies

GnomAD3 genomes
AF:
0.000445
AC:
50
AN:
112479
Hom.:
0
Cov.:
23
AF XY:
0.000260
AC XY:
9
AN XY:
34637
show subpopulations
Gnomad AFR
AF:
0.000291
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000281
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000162
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000732
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
24
AN:
183475
Hom.:
0
AF XY:
0.000162
AC XY:
11
AN XY:
67913
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000729
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000216
Gnomad SAS exome
AF:
0.000157
Gnomad FIN exome
AF:
0.0000625
Gnomad NFE exome
AF:
0.000171
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.000598
AC:
656
AN:
1097050
Hom.:
1
Cov.:
33
AF XY:
0.000955
AC XY:
347
AN XY:
363514
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
Gnomad4 AMR exome
AF:
0.000114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000298
Gnomad4 SAS exome
AF:
0.000536
Gnomad4 FIN exome
AF:
0.000321
Gnomad4 NFE exome
AF:
0.000671
Gnomad4 OTH exome
AF:
0.000282
GnomAD4 genome
AF:
0.000444
AC:
50
AN:
112535
Hom.:
0
Cov.:
23
AF XY:
0.000259
AC XY:
9
AN XY:
34701
show subpopulations
Gnomad4 AFR
AF:
0.000290
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000282
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000162
Gnomad4 NFE
AF:
0.000732
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000790
Hom.:
6

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Nov 22, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.68
T
BayesDel_noAF
Benign
-0.93
CADD
Benign
0.090
DANN
Benign
0.39
DEOGEN2
Benign
0.0020
T;T
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.050
.;T
M_CAP
Benign
0.0011
T
MetaRNN
Benign
0.053
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
0.44
N;N
REVEL
Benign
0.11
Sift
Benign
0.38
T;T
Sift4G
Benign
0.24
T;T
Polyphen
0.0
B;B
Vest4
0.067
MVP
0.58
MPC
0.94
ClinPred
0.013
T
GERP RS
-0.45
Varity_R
0.051
gMVP
0.087

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.

Other links and lift over

dbSNP: rs200647197; hg19: chrX-102755038; API