Variant X-48560746-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002536.4(TBC1D25):c.1838G>A(p.Arg613Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,209,809 control chromosomes in the GnomAD database, including 2 homozygotes. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.00019 ( 2 hom. 63 hem. )

Consequence

TBC1D25
NM_002536.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84

Variant links:

Genes affected

TBC1D25 (HGNC:8092): (TBC1 domain family member 25) This gene encodes a protein with a TBC domain and functions as a Rab GTPase activating protein. The encoded protein is involved in the fusion of autophagosomes with endosomes and lysosomes. This gene was previously known as ornithine aminotransferase-like 1, but has no similarity to ornithine aminotransferase. [provided by RefSeq, Jan 2017]

TBC1D25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017703056).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D25	NM_002536.4 linkuse as main transcript	c.1838G>A	p.Arg613Gln	missense_variant	6/6	ENST00000376771.9	NP_002527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D25	ENST00000376771.9 linkuse as main transcript	c.1838G>A	p.Arg613Gln	missense_variant	6/6	1	NM_002536.4	ENSP00000365962	P1	Q3MII6-1

Frequencies

GnomAD3 genomes

AF:

0.0000888

AC:

AN:

112603

Hom.:

Cov.:

AF XY:

0.0000575

AC XY:

AN XY:

34779

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000362

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000769

AC:

AN:

182153

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

66739

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 SAS exome

AF:

0.000477

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000185

AC:

203

AN:

1097154

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

362586

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000519

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.0000888

AC:

AN:

112655

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

34841

show subpopulations

Gnomad4 AFR

AF:

0.0000321

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000363

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.1838G>A (p.R613Q) alteration is located in exon 6 (coding exon 6) of the TBC1D25 gene. This alteration results from a G to A substitution at nucleotide position 1838, causing the arginine (R) at amino acid position 613 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.012

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.016

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.84

REVEL

Benign

0.043

Sift

Benign

0.29

Sift4G

Benign

0.39

Polyphen

0.0020

Vest4

0.032

MutPred

0.44

Gain of relative solvent accessibility (P = 0.09);

MVP

0.19

MPC

0.92

ClinPred

0.026

GERP RS

3.3

Varity_R

0.11

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over