Genetic Variant TBC1D25:p.Gln451Glu (chrX-48560259-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002536.4(TBC1D25):c.1351C>G(p.Gln451Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,097,915 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 8 hem. )

Consequence

TBC1D25
NM_002536.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06929764).

BS2

High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D25	NM_002536.4 link	c.1351C>G	p.Gln451Glu	missense_variant	Exon 6 of 6	ENST00000376771.9	NP_002527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D25	ENST00000376771.9 link	c.1351C>G	p.Gln451Glu	missense_variant	Exon 6 of 6	1	NM_002536.4	ENSP00000365962.4		Q3MII6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000221

AC:

AN:

181238

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1097915

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363283

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26398

American (AMR)

AF:

0.0000853

AC:

AN:

35170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40491

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

841995

Other (OTH)

AF:

0.0000217

AC:

AN:

46076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1351C>G (p.Q451E) alteration is located in exon 6 (coding exon 6) of the TBC1D25 gene. This alteration results from a C to G substitution at nucleotide position 1351, causing the glutamine (Q) at amino acid position 451 to be replaced by a glutamic acid (E). 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

0.065

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0068

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

M_CAP

Benign

0.0063

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.46

PhyloP100

1.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.16

REVEL

Benign

0.13

Sift

Benign

0.77

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.073

MutPred

0.23

Gain of glycosylation at S450 (P = 0.0809);

MVP

0.28

MPC

0.86

ClinPred

0.028

GERP RS

5.4

Varity_R

0.12

gMVP

0.51

Mutation Taster

=92/8

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over