Variant 17-42128365-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004583.4(RAB5C):c.337A>C(p.Lys113Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 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: 6.8e-7 ( 0 hom. )

Consequence

RAB5C
NM_004583.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99

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:

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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, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RAB5C	NM_004583.4 linkuse as main transcript	c.337A>C	p.Lys113Gln	missense_variant	4/6	ENST00000346213.9	NP_004574.2
RAB5C	NM_001252039.2 linkuse as main transcript	c.436A>C	p.Lys146Gln	missense_variant	5/7		NP_001238968.1
RAB5C	NM_201434.3 linkuse as main transcript	c.337A>C	p.Lys113Gln	missense_variant	5/7		NP_958842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB5C	ENST00000346213.9 linkuse as main transcript	c.337A>C	p.Lys113Gln	missense_variant	4/6	1	NM_004583.4	ENSP00000345689	P1	P51148-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727130

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.337A>C (p.K113Q) alteration is located in exon 5 (coding exon 3) of the RAB5C gene. This alteration results from a A to C substitution at nucleotide position 337, causing the lysine (K) at amino acid position 113 to be replaced by a glutamine (Q). 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

0.23

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

.;D;D;.;.;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.;D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

0.48

.;N;N;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.1

.;D;D;D;.;D

REVEL

Uncertain

0.64

Sift

Benign

0.11

.;T;T;T;.;T

Sift4G

Benign

0.17

T;T;T;T;T;T

Polyphen

1.0

.;D;D;.;.;.

Vest4

0.76, 0.72, 0.72

MutPred

0.57

Loss of methylation at K113 (P = 0.0126);Loss of methylation at K113 (P = 0.0126);Loss of methylation at K113 (P = 0.0126);.;.;Loss of methylation at K113 (P = 0.0126);

MVP

0.63

MPC

0.76

ClinPred

0.82

GERP RS

5.3

Varity_R

0.82

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over