Genetic Variant RAB5C:p.Tyr101Cys (chr17-42128665-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

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

The NM_004583.4(RAB5C):c.302A>G(p.Tyr101Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000446 in 1,344,254 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: 0.0000045 ( 0 hom. )

Consequence

RAB5C
NM_004583.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

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:

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, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5C	NM_004583.4 link	c.302A>G	p.Tyr101Cys	missense_variant	Exon 3 of 6	ENST00000346213.9	NP_004574.2	P51148-1A0A024R1U4
RAB5C	NM_001252039.2 link	c.401A>G	p.Tyr134Cys	missense_variant	Exon 4 of 7		NP_001238968.1	P51148-2
RAB5C	NM_201434.3 link	c.302A>G	p.Tyr101Cys	missense_variant	Exon 4 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.302A>G	p.Tyr101Cys	missense_variant	Exon 3 of 6	1	NM_004583.4	ENSP00000345689.5		P51148-1
ENSG00000267261	ENST00000592574.1 link	c.302A>G	p.Tyr101Cys	missense_variant	Exon 3 of 8	5		ENSP00000468367.1		K7ERQ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

166874

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

88950

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:

0.0000241

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000446

AC:

AN:

1344254

Hom.:

Cov.:

AF XY:

0.00000757

AC XY:

AN XY:

660168

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:

0.00000568

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.302A>G (p.Y101C) alteration is located in exon 4 (coding exon 2) of the RAB5C gene. This alteration results from a A to G substitution at nucleotide position 302, causing the tyrosine (Y) at amino acid position 101 to be replaced by a cysteine (C). 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

0.92

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D;D;.;.;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;.;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.8

.;M;M;.;.;.

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-8.1

.;D;D;D;.;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

.;D;D;.;.;.

Vest4

0.80, 0.90, 0.89

MutPred

0.83

Loss of phosphorylation at Y101 (P = 0.0626);Loss of phosphorylation at Y101 (P = 0.0626);Loss of phosphorylation at Y101 (P = 0.0626);.;.;Loss of phosphorylation at Y101 (P = 0.0626);

MVP

0.66

MPC

1.7

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: 5

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