12-71913836-A-T

Variant names:

• chr12-71913836-A-T
• rs3759171
• NM_001146213.3:c.1311A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001146213.3(TBC1D15):​c.1311A>T​(p.Gln437His) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBC1D15 NM_001146213.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71
• Publications: 30 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D15	NM_001146213.3	MANE Select	c.1311A>T	p.Gln437His	missense	Exon 12 of 17	NP_001139685.2
	TBC1D15	NM_022771.6		c.1362A>T	p.Gln454His	missense	Exon 13 of 18	NP_073608.4
	TBC1D15	NM_001385848.1		c.1311A>T	p.Gln437His	missense	Exon 12 of 17	NP_001372777.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D15	ENST00000485960.7	TSL:1 MANE Select	c.1311A>T	p.Gln437His	missense	Exon 12 of 17	ENSP00000420678.2
	TBC1D15	ENST00000550746.5	TSL:1	c.1362A>T	p.Gln454His	missense	Exon 13 of 18	ENSP00000448182.1
	TBC1D15	ENST00000462788.6	TSL:1	n.*725A>T		non_coding_transcript_exon	Exon 11 of 16	ENSP00000418467.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418114 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 705470

African (AFR) AF: 0.00 AC: 0 AN: 29634

American (AMR) AF: 0.00 AC: 0 AN: 33686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24878

East Asian (EAS) AF: 0.00 AC: 0 AN: 37048

South Asian (SAS) AF: 0.00 AC: 0 AN: 79006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096878

Other (OTH) AF: 0.00 AC: 0 AN: 58498

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 49364

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.0062
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		2.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Gain of catalytic residue at M456 (P = 0.0916)
MVP		0.57
MPC		0.60
ClinPred		1.0	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3759171; hg19: chr12-72307616;