Variant X-48545020-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002536.4(TBC1D25):c.385G>A(p.Asp129Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,202,294 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

TBC1D25
NM_002536.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.07

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3299022).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D25	NM_002536.4 linkuse as main transcript	c.385G>A	p.Asp129Asn	missense_variant	3/6	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.385G>A	p.Asp129Asn	missense_variant	3/6	1	NM_002536.4	ENSP00000365962	P1	Q3MII6-1

Frequencies

GnomAD3 genomes

AF:

0.0000285

AC:

AN:

105277

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

30481

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000598

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1097017

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

362589

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000285

AC:

AN:

105277

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

30481

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000598

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000264

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

Apr 26, 2023

The c.385G>A (p.D129N) alteration is located in exon 3 (coding exon 3) of the TBC1D25 gene. This alteration results from a G to A substitution at nucleotide position 385, causing the aspartic acid (D) at amino acid position 129 to be replaced by an asparagine (N). 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

0.18

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.044

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.050

T;D

Polyphen

0.99

D;.

Vest4

0.20

MutPred

0.34

Gain of catalytic residue at D129 (P = 0.0581);.;

MVP

0.65

MPC

1.7

ClinPred

0.97

GERP RS

5.6

Varity_R

0.22

gMVP

0.54

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