X-103500324-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_080879.3(RAB40A):​c.433G>C​(p.Ala145Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,210,292 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

8
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.59
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_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB40ANM_080879.3 linkc.433G>C p.Ala145Pro 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.433G>C p.Ala145Pro missense_variant Exon 3 of 3 2 NM_080879.3 ENSP00000305648.1 Q8WXH6

Frequencies

GnomAD3 genomes
AF:
0.0000268
AC:
3
AN:
112082
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
AN XY:
34240
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:
0.0000565
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1098210
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
363576
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000237
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000268
AC:
3
AN:
112082
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
AN XY:
34240
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:
0.0000565
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.433G>C (p.A145P) alteration is located in exon 3 (coding exon 1) of the RAB40A gene. This alteration results from a G to C substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 to be replaced by a proline (P). 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
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;D
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.97
.;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Pathogenic
3.3
M;M
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.62
MutPred
0.86
Gain of glycosylation at A145 (P = 0.0625);Gain of glycosylation at A145 (P = 0.0625);
MVP
0.99
MPC
2.1
ClinPred
1.0
D
GERP RS
0.23
Varity_R
0.98
gMVP
0.95

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: rs764858205; hg19: chrX-102755252; API