dbSNP rs72768728: TBC1D24:p.Phe295Leu (chr16-2497033-C-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199107.2(TBC1D24):c.885C>G(p.Phe295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00927 in 1,613,604 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 93 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.710

Publications

13 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Ambry Genetics
familial infantile myoclonic epilepsy
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
autosomal dominant nonsyndromic hearing loss 65
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
autosomal recessive nonsyndromic hearing loss 86
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
developmental and epileptic encephalopathy, 16
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
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

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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001199107.2

BP4

Computational evidence support a benign effect (MetaRNN=0.00785768).

BP6

Variant 16-2497033-C-G is Benign according to our data. Variant chr16-2497033-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00578 (880/152370) while in subpopulation NFE AF = 0.011 (748/68032). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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.885C>G	p.Phe295Leu	missense	Exon 2 of 8	NP_001186036.1	Q9ULP9-1
	TBC1D24	NM_020705.3		c.885C>G	p.Phe295Leu	missense	Exon 2 of 7	NP_065756.1	Q9ULP9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D24	ENST00000646147.1	MANE Select	c.885C>G	p.Phe295Leu	missense	Exon 2 of 8	ENSP00000494678.1	Q9ULP9-1
TBC1D24	ENST00000567020.7	TSL:1	c.885C>G	p.Phe295Leu	missense	Exon 2 of 7	ENSP00000454408.1	Q9ULP9-2
ENSG00000260272	ENST00000564543.1	TSL:2	c.885C>G	p.Phe295Leu	missense	Exon 1 of 3	ENSP00000455547.1	H3BQ06

Frequencies

GnomAD3 genomes

AF:

0.00578

AC:

880

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00532

AC:

1322

AN:

248578

AF XY:

0.00552

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000523

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00964

AC:

14086

AN:

1461234

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

6764

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000649

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000815

AC:

AN:

52770

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0121

AC:

13500

AN:

1112006

Other (OTH)

AF:

0.00604

AC:

365

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

882

1764

2646

3528

4410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.00578

AC:

880

AN:

152370

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

390

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41590

American (AMR)

AF:

0.00189

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

748

AN:

68032

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00785

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00210

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00556

AC:

674

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00845

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (6)

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

Familial infantile myoclonic epilepsy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0032

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.96

PhyloP100

0.71

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.45

REVEL

Benign

0.074

Sift

Benign

1.0

Sift4G

Benign

0.47

Polyphen

0.088

Vest4

0.36

MutPred

0.56

Gain of helix (P = 0.0696)

MVP

0.45

MPC

0.41

ClinPred

0.0035

GERP RS

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.65

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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