rs45479896

Positions:

chr6-57196547-A-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

RAB23 (HGNC:):

RAB23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 357644.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr6-57196547-A-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB23	NM_016277.5 linkuse as main transcript	c.301T>G	p.Ser101Ala	missense_variant	4/7	ENST00000468148.6	NP_057361.3	Q9ULC3A0A024RD41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6 linkuse as main transcript	c.301T>G	p.Ser101Ala	missense_variant	4/7	1	NM_016277.5	ENSP00000417610.1		Q9ULC3
RAB23	ENST00000317483.4 linkuse as main transcript	c.301T>G	p.Ser101Ala	missense_variant	4/7	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

GnomAD3 exomes

AF:

0.00600

AC:

1507

AN:

251026

Hom.:

AF XY:

0.00601

AC XY:

815

AN XY:

135690

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 SAS exome

AF:

0.00382

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

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00416

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.00780

Gnomad4 OTH exome

AF:

0.00702

GnomAD4 genome

AF:

0.00582

AC:

886

AN:

152316

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

428

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.00845

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00795

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RAB23: BP4, BS2 -

Carpenter syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

RAB23-related Carpenter syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

RAB23-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

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

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

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

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

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