rs104894500
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_183235.3(RAB27A):c.352C>T(p.Gln118Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,424,198 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
RAB27A
NM_183235.3 stop_gained
NM_183235.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.88
Genes affected
RAB27A (HGNC:9766): (RAB27A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-55224004-G-A is Pathogenic according to our data. Variant chr15-55224004-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAB27A | NM_183235.3 | c.352C>T | p.Gln118Ter | stop_gained | 6/7 | ENST00000336787.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAB27A | ENST00000336787.6 | c.352C>T | p.Gln118Ter | stop_gained | 6/7 | 1 | NM_183235.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000351 AC: 5AN: 1424198Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2AN XY: 710294
GnomAD4 exome
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1424198
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30
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2
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710294
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Griscelli syndrome type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | This sequence change creates a premature translational stop signal (p.Gln118*) in the RAB27A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB27A are known to be pathogenic (PMID: 10835631, 23160464). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Griscelli syndrome (PMID: 15163896, 23160464). ClinVar contains an entry for this variant (Variation ID: 5990). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 05, 2020 | ACMG classification criteria: PVS1, PS4, PM2, PM3 - |
Multisystem inflammatory syndrome in children Other:1
risk factor, no assertion criteria provided | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Nov 14, 2021 | - - |
Computational scores
Source:
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;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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