rs749994791

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_001199107.2(TBC1D24):​c.1525G>A​(p.Gly509Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,559,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense, splice_region

Scores

15
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.68
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 16-2500490-G-A is Pathogenic according to our data. Variant chr16-2500490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425091.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBC1D24NM_001199107.2 linkc.1525G>A p.Gly509Arg missense_variant, splice_region_variant 7/8 ENST00000646147.1 NP_001186036.1 Q9ULP9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBC1D24ENST00000646147.1 linkc.1525G>A p.Gly509Arg missense_variant, splice_region_variant 7/8 NM_001199107.2 ENSP00000494678.1 Q9ULP9-1
ENSG00000260272ENST00000564543.1 linkc.965+3377G>A intron_variant 2 ENSP00000455547.1 H3BQ06

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000194
AC:
3
AN:
155022
Hom.:
0
AF XY:
0.0000119
AC XY:
1
AN XY:
83830
show subpopulations
Gnomad AFR exome
AF:
0.000122
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000341
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000569
AC:
8
AN:
1407132
Hom.:
0
Cov.:
33
AF XY:
0.00000575
AC XY:
4
AN XY:
695454
show subpopulations
Gnomad4 AFR exome
AF:
0.0000311
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000547
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000461
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000955
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000348
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 16 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenJan 27, 2023- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2016- -
Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 31, 2022This variant is present in population databases (rs749994791, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 509 of the TBC1D24 protein (p.Gly509Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 425091). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
.;T;T;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
.;H;H;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.3
D;.;D;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;.;D;.
Sift4G
Pathogenic
0.0
D;.;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.81
MutPred
0.87
.;Gain of methylation at G509 (P = 0.0528);Gain of methylation at G509 (P = 0.0528);.;
MVP
0.99
MPC
1.2
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.94
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.33
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.33
Position offset: -4

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.

Other links and lift over

dbSNP: rs749994791; hg19: chr16-2550491; API