rs45479896

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016277.5(RAB23):c.301T>G(p.Ser101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,614,042 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 54 hom. )

Consequence

RAB23
NM_016277.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.20

Publications

10 publications found

Variant links:

Genes affected

RAB23 (HGNC:14263): (RAB23, member RAS oncogene family) This gene encodes a small GTPase of the Ras superfamily. Rab proteins are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. The encoded protein may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Disruption of this gene has been implicated in Carpenter syndrome as well as cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAB23 Gene-Disease associations (from GenCC):

RAB23-related Carpenter syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Carpenter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAB23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074023604).

BP6

Variant 6-57196547-A-C is Benign according to our data. Variant chr6-57196547-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357644.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00582 (886/152316) while in subpopulation NFE AF = 0.00845 (575/68020). AF 95% confidence interval is 0.00788. There are 8 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB23	NM_016277.5 link	c.301T>G	p.Ser101Ala	missense_variant	Exon 4 of 7	ENST00000468148.6	NP_057361.3	Q9ULC3A0A024RD41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6 link	c.301T>G	p.Ser101Ala	missense_variant	Exon 4 of 7	1	NM_016277.5	ENSP00000417610.1		Q9ULC3
RAB23	ENST00000317483.4 link	c.301T>G	p.Ser101Ala	missense_variant	Exon 4 of 7	1		ENSP00000320413.3		Q9ULC3

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

886

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00845

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00600

AC:

1507

AN:

251026

AF XY:

0.00601

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.00876

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00701

AC:

10252

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

5050

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33476

American (AMR)

AF:

0.00284

AC:

127

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000842

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39660

South Asian (SAS)

AF:

0.00416

AC:

359

AN:

86252

European-Finnish (FIN)

AF:

0.0111

AC:

592

AN:

53400

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00780

AC:

8671

AN:

1111946

Other (OTH)

AF:

0.00702

AC:

424

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

553

1106

1660

2213

2766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00582

AC:

886

AN:

152316

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

428

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41586

American (AMR)

AF:

0.00458

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00845

AC:

575

AN:

68020

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00764

Hom.:

Bravo

AF:

0.00511

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00633

AC:

768

Asia WGS

AF:

0.00202

AC:

AN:

3476

EpiCase

AF:

0.00971

EpiControl

AF:

0.00848

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAB23: BP4, BS2 -

Jul 23, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Carpenter syndrome

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RAB23-related Carpenter syndrome

Benign:2

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

RAB23-related disorder

Benign:1

Sep 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

D;.

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

N;N

PhyloP100

1.2

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.14

Sift

Benign

0.58

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0

B;B

Vest4

0.24

MVP

0.72

MPC

0.15

ClinPred

0.0035

GERP RS

0.76

Varity_R

0.061

gMVP

0.22

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over