Genetic Variant RAB5B:p.Ser16Asn (chr12-55987007-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002868.4(RAB5B):c.47G>A(p.Ser16Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,413,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RAB5B
NM_002868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

Publications

0 publications found

Variant links:

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB5B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11621562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4 link	c.47G>A	p.Ser16Asn	missense_variant	Exon 2 of 6	ENST00000360299.10	NP_002859.1	P61020-1A0A024RB09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10 link	c.47G>A	p.Ser16Asn	missense_variant	Exon 2 of 6	1	NM_002868.4	ENSP00000353444.5		P61020-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251432

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1413358

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

702496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32024

American (AMR)

AF:

0.00

AC:

AN:

43008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

35670

South Asian (SAS)

AF:

0.00

AC:

AN:

85768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

1080416

Other (OTH)

AF:

0.00

AC:

AN:

57098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.47G>A (p.S16N) alteration is located in exon 2 (coding exon 1) of the RAB5B gene. This alteration results from a G to A substitution at nucleotide position 47, causing the serine (S) at amino acid position 16 to be replaced by an asparagine (N). 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

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.031

T;T;T;T;T;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

.;D;D;D;D;D;D

M_CAP

Benign

0.0078

MetaRNN

Benign

0.12

T;T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.36

N;N;.;.;.;N;.

PhyloP100

1.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.78

N;N;N;N;N;N;.

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;T;T;T;.

Sift4G

Benign

0.87

T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;.;.;.

Vest4

0.12

MutPred

0.35

Loss of disorder (P = 0.0973);Loss of disorder (P = 0.0973);Loss of disorder (P = 0.0973);.;Loss of disorder (P = 0.0973);Loss of disorder (P = 0.0973);Loss of disorder (P = 0.0973);

MVP

0.66

MPC

0.62

ClinPred

0.20

GERP RS

4.9

PromoterAI

0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.23

gMVP

0.31

Mutation Taster

=73/27

polymorphism

(source)

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

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chr12-55987007-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over