rs199700840

Variant names:

• chr16-2497026-G-A
• rs199700840
• NM_001199107.2:c.878G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2497026-G-A
• chr16-2497026-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM5

The NM_001199107.2(TBC1D24):​c.878G>A​(p.Arg293His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 9.93
• Publications: 12 publications found

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

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001199107.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2497025-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2507172.

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.878G>A	p.Arg293His	missense	Exon 2 of 8	NP_001186036.1	Q9ULP9-1
	TBC1D24	NM_020705.3		c.878G>A	p.Arg293His	missense	Exon 2 of 7	NP_065756.1	Q9ULP9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	ENST00000646147.1	MANE Select	c.878G>A	p.Arg293His	missense	Exon 2 of 8	ENSP00000494678.1	Q9ULP9-1
	TBC1D24	ENST00000567020.7	TSL:1	c.878G>A	p.Arg293His	missense	Exon 2 of 7	ENSP00000454408.1	Q9ULP9-2
	ENSG00000260272	ENST00000564543.1	TSL:2	c.878G>A	p.Arg293His	missense	Exon 1 of 3	ENSP00000455547.1	H3BQ06

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000193 AC: 48 AN: 248774 AF XY: 0.000193

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000334 AC: 488 AN: 1461288 Hom.: 0 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 726966

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000411 AC: 457 AN: 1112008

Other (OTH) AF: 0.000248 AC: 15 AN: 60392

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74508

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000821 AC: 7

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;na:Caused by mutation in the TBC1 domain family, member 24 (1)
-	1	-	DOORS syndrome;C0917800:Familial infantile myoclonic epilepsy;C1842531:Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome;C2829265:Autosomal recessive nonsyndromic hearing loss 86;C3809173:Developmental and epileptic encephalopathy, 16;C3892048:Autosomal dominant nonsyndromic hearing loss 65 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.81
MPC		1.2
ClinPred		0.80	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.78
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs199700840; hg19: chr16-2547027; COSMIC: COSV99036653; COSMIC: COSV99036653;