GeneBe

rs797044549

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001199107.2(TBC1D24):​c.1460dupA​(p.His487GlnfsTer71) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.86

Publications

6 publications found
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]
TBC1D24 Gene-Disease associations (from GenCC):
  • DOORS syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
  • familial infantile myoclonic epilepsy
    Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
  • autosomal dominant nonsyndromic hearing loss 65
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • malignant migrating partial seizures of infancy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • focal epilepsy-intellectual disability-cerebro-cerebellar malformation
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • progressive myoclonic epilepsy with dystonia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • nonsyndromic genetic hearing loss
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • autosomal recessive nonsyndromic hearing loss 86
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 16-2500424-C-CA is Pathogenic according to our data. Variant chr16-2500424-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 183156.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D24NM_001199107.2 linkc.1460dupA p.His487GlnfsTer71 frameshift_variant Exon 7 of 8 ENST00000646147.1 NP_001186036.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D24ENST00000646147.1 linkc.1460dupA p.His487GlnfsTer71 frameshift_variant Exon 7 of 8 NM_001199107.2 ENSP00000494678.1
ENSG00000260272ENST00000564543.1 linkc.965+3312dupA intron_variant Intron 1 of 2 2 ENSP00000455547.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1450134
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
720242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33230
American (AMR)
AF:
0.00
AC:
0
AN:
43612
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25816
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39136
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84092
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51470
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5732
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1107136
Other (OTH)
AF:
0.00
AC:
0
AN:
59910
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

DOORS syndrome Pathogenic:1
Dec 22, 2014
Division of Medical Genetics; Sainte-Justine Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
8.9
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044549; hg19: chr16-2550425; API