12-71897912-C-T

Variant names:

• chr12-71897912-C-T
• rs578222908
• NM_001146213.3:c.1154C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146213.3(TBC1D15):​c.1154C>T​(p.Ser385Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TBC1D15 NM_001146213.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88
• Publications: 2 publications found

Genes affected

TBC1D15 (HGNC:25694): (TBC1 domain family member 15) This gene encodes a member of the Ras-like proteins in brain-GTPase activating protein superfamily that share a conserved Tre-2/Bub2/Cdc16 domain. The encoded protein interacts with Ras-like protein in brain 5A and may function as a regulator of intracellular trafficking. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2915907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146213.3. 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
	TBC1D15	NM_001146213.3	MANE Select	c.1154C>T	p.Ser385Leu	missense	Exon 10 of 17	NP_001139685.2	Q8TC07-2
	TBC1D15	NM_022771.6		c.1205C>T	p.Ser402Leu	missense	Exon 11 of 18	NP_073608.4
	TBC1D15	NM_001385848.1		c.1154C>T	p.Ser385Leu	missense	Exon 10 of 17	NP_001372777.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D15	ENST00000485960.7	TSL:1 MANE Select	c.1154C>T	p.Ser385Leu	missense	Exon 10 of 17	ENSP00000420678.2	Q8TC07-2
	TBC1D15	ENST00000550746.5	TSL:1	c.1205C>T	p.Ser402Leu	missense	Exon 11 of 18	ENSP00000448182.1	Q8TC07-1
	TBC1D15	ENST00000462788.6	TSL:1	n.*568C>T		non_coding_transcript_exon	Exon 9 of 16	ENSP00000418467.2	F8WCB5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 250798 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460284 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726522

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39484

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111026

Other (OTH) AF: 0.0000332 AC: 2 AN: 60320

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41510

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.57	P
Vest4		0.55
MVP		0.49
MPC		0.29
ClinPred		0.67	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.60
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs578222908; hg19: chr12-72291692; COSMIC: COSV59847794; COSMIC: COSV59847794;