chr16-2499425-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_001199107.2(TBC1D24):c.1206+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000205 in 1,460,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TBC1D24
NM_001199107.2 splice_donor_5th_base, intron
NM_001199107.2 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9987
2
Clinical Significance
Conservation
PhyloP100: 7.15
Genes affected
TBC1D24 (HGNC:29203): (TBC1 domain family member 24) This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 16-2499425-G-A is Pathogenic according to our data. Variant chr16-2499425-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91399.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2499425-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D24 | NM_001199107.2 | c.1206+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000646147.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.1206+5G>A | splice_donor_5th_base_variant, intron_variant | NM_001199107.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460848Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726676
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31
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2
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
DOORS syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jan 01, 2014 | We identified 26 families with DOORS syndrome; each patient had at least 3 of the 5 well-described features of DOORS syndrome, which include deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. A combination of whole-exome sequencing and Sanger sequencing identified homozygous or compound heterozygous pathogenic variants in TBC1D24 in 11 individuals from 9 families. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at