chr16-2495790-T-A

Variant names:

• chr16-2495790-T-A
• rs59034110
• NM_001199107.2:c.-115-244T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001199107.2(TBC1D24):​c.-115-244T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 151,158 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0081 (17 hom., cov: 33)
• Consequence: TBC1D24 NM_001199107.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.295
• Publications: 0 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: 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

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-2495790-T-A is Benign according to our data. Variant chr16-2495790-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 677586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00806 (1218/151158) while in subpopulation AFR AF = 0.0275 (1131/41104). AF 95% confidence interval is 0.0262. There are 17 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.-115-244T>A		intron_variant	Intron 1 of 7	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.-115-244T>A		intron_variant	Intron 1 of 7		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.-359T>A		upstream_gene_variant		2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1215 AN: 151038 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00409

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00827

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00806 AC: 1218 AN: 151158 Hom.: 17 Cov.: 33 AF XY: 0.00780 AC XY: 576 AN XY: 73840

African (AFR) AF: 0.0275 AC: 1131 AN: 41104

American (AMR) AF: 0.00408 AC: 62 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67758

Other (OTH) AF: 0.00818 AC: 17 AN: 2078

Alfa AF: 0.00603 Hom.: 2

Bravo AF: 0.00932

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.4
DANN	Benign	0.47
PhyloP100		0.29
PromoterAI		-0.0052	Neutral
Mutation Taster		=100/0	polymorphism

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: rs59034110; hg19: chr16-2545791;