chr17-42128308-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004583.4(RAB5C):​c.394G>A​(p.Ala132Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,790 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: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RAB5C
NM_004583.4 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90
Variant links:
Genes affected
RAB5C (HGNC:9785): (RAB5C, member RAS oncogene family) Members of the Rab protein family are small GTPases of the Ras superfamily that are thought to ensure fidelity in the process of docking and/or fusion of vesicles with their correct acceptor compartment (Han et al., 1996 [PubMed 8646882]).[supplied by OMIM, Nov 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB5CNM_004583.4 linkc.394G>A p.Ala132Thr missense_variant Exon 4 of 6 ENST00000346213.9 NP_004574.2 P51148-1A0A024R1U4
RAB5CNM_001252039.2 linkc.493G>A p.Ala165Thr missense_variant Exon 5 of 7 NP_001238968.1 P51148-2
RAB5CNM_201434.3 linkc.394G>A p.Ala132Thr missense_variant Exon 5 of 7 NP_958842.1 P51148-1A0A024R1U4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAB5CENST00000346213.9 linkc.394G>A p.Ala132Thr missense_variant Exon 4 of 6 1 NM_004583.4 ENSP00000345689.5 P51148-1
ENSG00000267261ENST00000592574.1 linkc.394G>A p.Ala132Thr missense_variant Exon 4 of 8 5 ENSP00000468367.1 K7ERQ8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251262
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461790
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 11, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.394G>A (p.A132T) alteration is located in exon 5 (coding exon 3) of the RAB5C gene. This alteration results from a G to A substitution at nucleotide position 394, causing the alanine (A) at amino acid position 132 to be replaced by a threonine (T). 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
0.65
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
.;D;D;.;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D;.;D;D;D
M_CAP
Benign
0.071
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Uncertain
2.4
.;M;M;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.5
.;D;D;D;.
REVEL
Uncertain
0.52
Sift
Uncertain
0.0060
.;D;D;D;.
Sift4G
Benign
0.092
T;D;D;D;D
Polyphen
0.18
.;B;B;.;.
Vest4
0.66, 0.68, 0.68
MutPred
0.56
Loss of ubiquitination at K135 (P = 0.0747);Loss of ubiquitination at K135 (P = 0.0747);Loss of ubiquitination at K135 (P = 0.0747);.;.;
MVP
0.65
MPC
1.4
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.50
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs1028172671; hg19: chr17-40280326; API