chr10-94403100-T-G

Position:

• chr10-94403100-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015188.2(TBC1D12):​c.487T>G​(p.Ser163Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: TBC1D12 NM_015188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.170

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]

ACMG classification

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=0.0356597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D12	NM_015188.2	c.487T>G	p.Ser163Ala	missense_variant	1/13	ENST00000225235.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D12	ENST00000225235.5	c.487T>G	p.Ser163Ala	missense_variant	1/13	1	NM_015188.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.487T>G (p.S163A) alteration is located in exon 1 (coding exon 1) of the TBC1D12 gene. This alteration results from a T to G substitution at nucleotide position 487, causing the serine (S) at amino acid position 163 to be replaced by an alanine (A). 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	0.057
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.47
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.018
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0090	B
Vest4		0.054
MutPred		0.14		Loss of phosphorylation at S163 (P = 4e-04);
MVP		0.24
MPC		0.40
ClinPred		0.048	T
GERP RS		0.85
Varity_R		0.052
gMVP		0.039

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

Other links and lift over

dbSNP: rs1347051634; hg19: chr10-96162857;