18-8609764-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001025300.3(RAB12):​c.325G>A​(p.Gly109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,268,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

RAB12
NM_001025300.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82
Variant links:
Genes affected
RAB12 (HGNC:31332): (RAB12, member RAS oncogene family) Enables GDP binding activity. Predicted to be involved in several processes, including cellular response to insulin stimulus; endosome to lysosome transport; and secretion by cell. Predicted to act upstream of or within cellular response to interferon-gamma. Predicted to be located in lysosome; phagocytic vesicle; and recycling endosome membrane. Predicted to be active in Golgi apparatus; cytoplasmic vesicle; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.111762464).
BS2
High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAB12NM_001025300.3 linkc.325G>A p.Gly109Ser missense_variant 1/6 ENST00000649141.2 NP_001020471.3 Q6IQ22
RAB12XR_001753165.2 linkn.328G>A non_coding_transcript_exon_variant 1/4
RAB12XR_001753166.2 linkn.328G>A non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAB12ENST00000649141.2 linkc.325G>A p.Gly109Ser missense_variant 1/6 NM_001025300.3 ENSP00000497886.1 A0A3B3ITT1

Frequencies

GnomAD3 genomes
AF:
0.000680
AC:
102
AN:
149900
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00238
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000133
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:
0.00
Gnomad OTH
AF:
0.000973
GnomAD4 exome
AF:
0.0000465
AC:
52
AN:
1118306
Hom.:
0
Cov.:
30
AF XY:
0.0000355
AC XY:
19
AN XY:
535698
show subpopulations
Gnomad4 AFR exome
AF:
0.00180
Gnomad4 AMR exome
AF:
0.000258
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:
0.00000213
Gnomad4 OTH exome
AF:
0.000181
GnomAD4 genome
AF:
0.000687
AC:
103
AN:
150006
Hom.:
0
Cov.:
32
AF XY:
0.000723
AC XY:
53
AN XY:
73262
show subpopulations
Gnomad4 AFR
AF:
0.00240
Gnomad4 AMR
AF:
0.000133
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000962
Alfa
AF:
0.000427
Hom.:
0
Bravo
AF:
0.000842

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The c.37G>A (p.G13S) alteration is located in exon 1 (coding exon 1) of the RAB12 gene. This alteration results from a G to A substitution at nucleotide position 37, causing the glycine (G) at amino acid position 13 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
0.17
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.028
.;T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.67
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.63
T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
.;N
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.11
.;N
REVEL
Benign
0.097
Sift
Uncertain
0.016
.;D
Sift4G
Uncertain
0.017
.;D
Polyphen
0.13
.;B
Vest4
0.27
MutPred
0.27
.;Gain of glycosylation at G13 (P = 8e-04);
MVP
0.55
MPC
1.5
ClinPred
0.77
D
GERP RS
2.6
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
4.3
Varity_R
0.16
gMVP
0.37

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: rs889464653; hg19: chr18-8609762; API