dbSNP rs201059992: TBC1D24:p.Ala500Ala (chr16-2500465-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001199107.2(TBC1D24):c.1500G>A(p.Ala500Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,580,046 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A500A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

TBC1D24
NM_001199107.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -4.23

Publications

2 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

TBC1D24 links:

ENSG00000260272 (HGNC:):

ENSG00000260272 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 16-2500465-G-A is Benign according to our data. Variant chr16-2500465-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00317 (483/152310) while in subpopulation NFE AF = 0.00465 (316/68020). AF 95% confidence interval is 0.00422. There are 0 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199107.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	NM_001199107.2	MANE Select	c.1500G>A	p.Ala500Ala	synonymous	Exon 7 of 8	NP_001186036.1
	TBC1D24	NM_020705.3		c.1482G>A	p.Ala494Ala	synonymous	Exon 6 of 7	NP_065756.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBC1D24	ENST00000646147.1	MANE Select	c.1500G>A	p.Ala500Ala	synonymous	Exon 7 of 8	ENSP00000494678.1
TBC1D24	ENST00000567020.7	TSL:1	c.1482G>A	p.Ala494Ala	synonymous	Exon 6 of 7	ENSP00000454408.1
ENSG00000260272	ENST00000564543.1	TSL:2	c.965+3352G>A		intron	N/A	ENSP00000455547.1

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

483

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00465

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00315

AC:

577

AN:

183344

AF XY:

0.00316

show subpopulations

Gnomad AFR exome

AF:

0.000794

Gnomad AMR exome

AF:

0.000346

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.00422

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00367

AC:

5236

AN:

1427736

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

2595

AN XY:

707546

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

32706

American (AMR)

AF:

0.000717

AC:

AN:

40472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25476

East Asian (EAS)

AF:

0.00

AC:

AN:

37700

South Asian (SAS)

AF:

0.000256

AC:

AN:

82062

European-Finnish (FIN)

AF:

0.0116

AC:

573

AN:

49234

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.00405

AC:

4432

AN:

1095492

Other (OTH)

AF:

0.00249

AC:

147

AN:

59062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

288

576

864

1152

1440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00317

AC:

483

AN:

152310

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

259

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41578

American (AMR)

AF:

0.00111

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0106

AC:

113

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00465

AC:

316

AN:

68020

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00322

Hom.:

Bravo

AF:

0.00211

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 (1)

Familial infantile myoclonic epilepsy (1)

Inborn genetic diseases (1)

TBC1D24-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.074

(source)

DANN

Benign

0.77

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over