rs121908171

chr6-57194817-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting

The NM_016277.5(RAB23):c.434T>A(p.Leu145Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,613,482 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L145L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

RAB23
NM_016277.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.36

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-57194817-A-T is Pathogenic according to our data. Variant chr6-57194817-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 4591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-57194817-A-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000592 (865/1461216) while in subpopulation NFE AF= 0.000751 (835/1111618). AF 95% confidence interval is 0.000709. There are 0 homozygotes in gnomad4_exome. There are 418 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB23	NM_016277.5 linkuse as main transcript	c.434T>A	p.Leu145Ter	stop_gained	5/7	ENST00000468148.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB23	ENST00000468148.6 linkuse as main transcript	c.434T>A	p.Leu145Ter	stop_gained	5/7	1	NM_016277.5	P1
RAB23	ENST00000317483.4 linkuse as main transcript	c.434T>A	p.Leu145Ter	stop_gained	5/7	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000283

AC:

AN:

250832

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000565

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000592

AC:

865

AN:

1461216

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

418

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000751

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000361

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000463

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RAB23-related Carpenter syndrome

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 06, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

RAB23-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2023

The RAB23 c.434T>A variant is predicted to result in premature protein termination (p.Leu145*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Carpenter syndrome (Jenkins et al. 2007. PubMed ID: 17503333; Jenkins et al. 2011. PubMed ID: 21412941; Salem et al. 2013. PubMed ID: 23599695). This variant is reported in 0.057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RAB23 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Carpenter syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Leu145*) in the RAB23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB23 are known to be pathogenic (PMID: 17503333, 21412941). This variant is present in population databases (rs121908171, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with Carpenter syndrome (PMID: 17503333, 21412941, 24458945). ClinVar contains an entry for this variant (Variation ID: 4591). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 23599695, 21412941, 24458945, 30487145, 25168863, 20358613, 31980526, 31589614, 17503333) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.65

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A

Vest4

0.97

GERP RS

5.9

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