Genetic Variant TBC1D12:p.Pro98Leu (chr10-94402906-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015188.2(TBC1D12):c.293C>T(p.Pro98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000214 in 1,493,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P98R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TBC1D12
NM_015188.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.178

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05180195).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015188.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D12	NM_015188.2	MANE Select	c.293C>T	p.Pro98Leu	missense	Exon 1 of 13	NP_056003.1	O60347

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D12	ENST00000225235.5	TSL:1 MANE Select	c.293C>T	p.Pro98Leu	missense	Exon 1 of 13	ENSP00000225235.4	O60347
TBC1D12	ENST00000971288.1		c.293C>T	p.Pro98Leu	missense	Exon 1 of 12	ENSP00000641347.1
TBC1D12	ENST00000904400.1		c.293C>T	p.Pro98Leu	missense	Exon 1 of 12	ENSP00000574459.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000172

AC:

AN:

81578

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1341350

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

660224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26718

American (AMR)

AF:

0.000572

AC:

AN:

26232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21668

East Asian (EAS)

AF:

0.00

AC:

AN:

32002

South Asian (SAS)

AF:

0.00

AC:

AN:

70690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.00000660

AC:

AN:

1060824

Other (OTH)

AF:

0.0000719

AC:

AN:

55670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000394

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000250

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

0.18

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.050

REVEL

Benign

0.047

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.032

Polyphen

0.0

Vest4

0.19

MutPred

0.14

Loss of glycosylation at P98 (P = 0.0171)

MVP

0.36

MPC

0.50

ClinPred

0.060

GERP RS

1.5

PromoterAI

0.060

Neutral

(source)

Varity_R

0.038

gMVP

0.064

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over