Genetic Variant TBC1D12:p.Tyr87Asn (chr10-94402872-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015188.2(TBC1D12):c.259T>A(p.Tyr87Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000587 in 1,363,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

TBC1D12
NM_015188.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0340

Variant links:

Genes affected

TBC1D12 (HGNC:29082): (TBC1 domain family member 12) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity; intracellular protein transport; and regulation of autophagosome assembly. Predicted to be active in autophagosome and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D12 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055485755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D12	NM_015188.2 link	c.259T>A	p.Tyr87Asn	missense_variant	Exon 1 of 13	ENST00000225235.5	NP_056003.1	O60347

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D12	ENST00000225235.5 link	c.259T>A	p.Tyr87Asn	missense_variant	Exon 1 of 13	1	NM_015188.2	ENSP00000225235.4		O60347

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000986

AC:

AN:

101428

Hom.:

AF XY:

0.00

AC XY:

AN XY:

55528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000129

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000587

AC:

AN:

1363428

Hom.:

Cov.:

AF XY:

0.00000447

AC XY:

AN XY:

671046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000589

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.37e-7

Gnomad4 OTH exome

AF:

0.0000883

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259T>A (p.Y87N) alteration is located in exon 1 (coding exon 1) of the TBC1D12 gene. This alteration results from a T to A substitution at nucleotide position 259, causing the tyrosine (Y) at amino acid position 87 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

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.0085

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.13

REVEL

Benign

0.014

Sift

Benign

0.037

Sift4G

Benign

0.25

Polyphen

0.0020

Vest4

0.20

MutPred

0.17

Loss of sheet (P = 0.0181);

MVP

0.30

MPC

0.81

ClinPred

0.021

GERP RS

-2.4

Varity_R

0.052

gMVP

0.068

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