Genetic Variant RAB5C:p.Ala132Thr (chr17-42128308-C-T) – ACMG Classification: Uncertain_significance (3 pts)

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

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]

RAB5C links:

ENSG00000267261 (HGNC:):

ENSG00000267261 links:

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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
RAB5C	NM_004583.4 link	c.394G>A	p.Ala132Thr	missense_variant	Exon 4 of 6	ENST00000346213.9	NP_004574.2	P51148-1A0A024R1U4
RAB5C	NM_001252039.2 link	c.493G>A	p.Ala165Thr	missense_variant	Exon 5 of 7		NP_001238968.1	P51148-2
RAB5C	NM_201434.3 link	c.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
RAB5C	ENST00000346213.9 link	c.394G>A	p.Ala132Thr	missense_variant	Exon 4 of 6	1	NM_004583.4	ENSP00000345689.5		P51148-1
ENSG00000267261	ENST00000592574.1 link	c.394G>A	p.Ala132Thr	missense_variant	Exon 4 of 8	5		ENSP00000468367.1		K7ERQ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251262

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

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.:

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

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

.;D;D;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.76

D;D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.4

.;M;M;.;.

PrimateAI

Pathogenic

0.86

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over