12-71894795-C-G

Variant names:

• chr12-71894795-C-G
• rs752890787
• NM_001146213.3:c.767C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146213.3(TBC1D15):​c.767C>G​(p.Pro256Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,176 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P256S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBC1D15 NM_001146213.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22517452).

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.767C>G	p.Pro256Arg	missense	Exon 7 of 17	NP_001139685.2	Q8TC07-2
	TBC1D15	NM_022771.6		c.818C>G	p.Pro273Arg	missense	Exon 8 of 18	NP_073608.4
	TBC1D15	NM_001385848.1		c.767C>G	p.Pro256Arg	missense	Exon 7 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.767C>G	p.Pro256Arg	missense	Exon 7 of 17	ENSP00000420678.2	Q8TC07-2
	TBC1D15	ENST00000550746.5	TSL:1	c.818C>G	p.Pro273Arg	missense	Exon 8 of 18	ENSP00000448182.1	Q8TC07-1
	TBC1D15	ENST00000491063.5	TSL:1	c.470C>G	p.Pro157Arg	missense	Exon 8 of 11	ENSP00000418091.1	C9JA93

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461176 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111494

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.090
Sift	Benign	0.49	T
Sift4G	Benign	0.52	T
Polyphen		0.013	B
Vest4		0.41
MutPred		0.16		Loss of catalytic residue at P272 (P = 0.0175)
MVP		0.52
MPC		0.18
ClinPred		0.75	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.71
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs752890787; hg19: chr12-72288575;