6-57194817-A-T
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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.Leu145*) 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 (★★). 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
NM_016277.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.36
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]
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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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RAB23 | NM_016277.5 | c.434T>A | p.Leu145* | stop_gained | 5/7 | ENST00000468148.6 | NP_057361.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RAB23 | ENST00000468148.6 | c.434T>A | p.Leu145* | stop_gained | 5/7 | 1 | NM_016277.5 | ENSP00000417610.1 | ||
| RAB23 | ENST00000317483.4 | c.434T>A | p.Leu145* | stop_gained | 5/7 | 1 | ENSP00000320413.3 |
Frequencies
GnomAD3 genomes 0.000361 AC: 55AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000283 AC: 71AN: 250832Hom.: 0 AF XY: 0.000273 AC XY: 37AN XY: 135558
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GnomAD4 exome AF: 0.000592 AC: 865AN: 1461216Hom.: 0 Cov.: 30 AF XY: 0.000575 AC XY: 418AN XY: 726910
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GnomAD4 genome 0.000361 AC: 55AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74460
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
RAB23-related Carpenter syndrome Pathogenic:8
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 02, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 16, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Jul 09, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Carpenter syndrome (MIM#201000). (I) 0115 - Variants in this gene are known to have variable expressivity. Main features are craniosynostosis, obesity, polydactyly, and soft-tissue syndactylyeatures; additional features are variable (PMID: 17503333). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 125 heterozygotes, 0 homozygotes). (SP) 0702 - Other variants predicted to cause NMD comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been regarded as pathogenic by multiple clinical laboratories in ClinVar and detected in many individuals with Carpenter syndrome, both homozygous and compound heterozygous (PMID: 17503333). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2014 | - - |
RAB23-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at