NM_001199107.2:c.*2G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001199107.2(TBC1D24):​c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,609,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 3_prime_UTR

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.126

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 16-2500960-G-A is Benign according to our data. Variant chr16-2500960-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229286.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D24NM_001199107.2 linkc.*2G>A 3_prime_UTR_variant Exon 8 of 8 ENST00000646147.1 NP_001186036.1 Q9ULP9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D24ENST00000646147.1 linkc.*2G>A 3_prime_UTR_variant Exon 8 of 8 NM_001199107.2 ENSP00000494678.1 Q9ULP9-1
ENSG00000260272ENST00000564543.1 linkc.965+3847G>A intron_variant Intron 1 of 2 2 ENSP00000455547.1 H3BQ06

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD2 exomes
AF:
0.00000819
AC:
2
AN:
244158
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000686
AC:
10
AN:
1457396
Hom.:
0
Cov.:
31
AF XY:
0.00000689
AC XY:
5
AN XY:
725272
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49168
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000809
AC:
9
AN:
1111874
Other (OTH)
AF:
0.00
AC:
0
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not provided Uncertain:1Benign:1
Nov 17, 2023
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Dec 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Jun 16, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.*2G>A variant in TBC1D24 has not been previously reported in individuals with hearing loss, b ut has been identified in 3/64658 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This variant occurs in the 3' UTR. This genomic region contains regulatory elements essential for the regulati on and transport of the mRNA transcript, and variants in this region could resul t in dysregulation or disruption of these functions. However, the c.*2 nucleotid e position is not conserved across mammals and evolutionarily distant species, m any of which, including 5 mammals, have an adenine (A) base at this position, su ggesting that this variant is tolerated. In summary, while the clinical signific ance of the c.*2G>A variant is uncertain, the conservation data suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.20
DANN
Benign
0.56
PhyloP100
0.13
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs780054979; hg19: chr16-2550961; API