15-73887675-T-C

Position:

• chr15-73887675-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153356.3(TBC1D21):​c.833T>C​(p.Met278Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D21 NM_153356.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

TBC1D21 (HGNC:28536): (TBC1 domain family member 21) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D21	NM_153356.3	c.833T>C	p.Met278Thr	missense_variant	9/11	ENST00000300504.7	NP_699187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D21	ENST00000300504.7	c.833T>C	p.Met278Thr	missense_variant	9/11	1	NM_153356.3	ENSP00000300504.2
TBC1D21	ENST00000535547.6	c.725T>C	p.Met242Thr	missense_variant	8/10	1		ENSP00000439325.2
TBC1D21	ENST00000562056.1	c.722T>C	p.Met241Thr	missense_variant	8/10	5		ENSP00000457096.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jul 15, 2024

The c.833T>C (p.M278T) alteration is located in exon 9 (coding exon 9) of the TBC1D21 gene. This alteration results from a T to C substitution at nucleotide position 833, causing the methionine (M) at amino acid position 278 to be replaced by a threonine (T). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.024	.;B;.
Vest4		0.72
MutPred		0.55		.;Gain of catalytic residue at M278 (P = 0.0372);.;
MVP		0.30
MPC		0.39
ClinPred		0.67	D
GERP RS		4.6
Varity_R		0.58
gMVP		0.79

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74180016;