chr12-120108461-C-T

Variant summary

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

The NM_006861.7(RAB35):​c.59G>A​(p.Gly20Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAB35
NM_006861.7 missense

Scores

17
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79
Variant links:
Genes affected
RAB35 (HGNC:9774): (RAB35, member RAS oncogene family) Enables GTPase activity; guanyl ribonucleotide binding activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including endosomal transport; plasma membrane to endosome transport; and protein localization to endosome. Located in several cellular components, including clathrin-coated endocytic vesicle; clathrin-coated pit; and intercellular bridge. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB35NM_006861.7 linkc.59G>A p.Gly20Asp missense_variant Exon 2 of 6 ENST00000229340.10 NP_006852.1 Q15286-1
RAB35NM_001167606.2 linkc.59G>A p.Gly20Asp missense_variant Exon 2 of 5 NP_001161078.1 Q15286-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAB35ENST00000229340.10 linkc.59G>A p.Gly20Asp missense_variant Exon 2 of 6 1 NM_006861.7 ENSP00000229340.5 Q15286-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461626
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727140
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.59G>A (p.G20D) alteration is located in exon 2 (coding exon 2) of the RAB35 gene. This alteration results from a G to A substitution at nucleotide position 59, causing the glycine (G) at amino acid position 20 to be replaced by an aspartic acid (D). 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
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.9
H;H;.
PrimateAI
Pathogenic
0.96
D
PROVEAN
Pathogenic
-6.1
D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.92
MutPred
0.89
Gain of ubiquitination at K21 (P = 0.0797);Gain of ubiquitination at K21 (P = 0.0797);Gain of ubiquitination at K21 (P = 0.0797);
MVP
0.99
MPC
2.7
ClinPred
0.99
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-120546265; API