15-73881672-C-G

Variant names:

• chr15-73881672-C-G
• rs534115621
• NM_153356.3:c.197C>G

Variant summary

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

The NM_153356.3(TBC1D21):​c.197C>G​(p.Ala66Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBC1D21 NM_153356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75

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 rank	MANE	Protein	UniProt
TBC1D21	NM_153356.3	c.197C>G	p.Ala66Gly	missense_variant	Exon 3 of 11	ENST00000300504.7	NP_699187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D21	ENST00000300504.7	c.197C>G	p.Ala66Gly	missense_variant	Exon 3 of 11	1	NM_153356.3	ENSP00000300504.2
TBC1D21	ENST00000535547.6	c.89C>G	p.Ala30Gly	missense_variant	Exon 2 of 10	1		ENSP00000439325.2
TBC1D21	ENST00000562056.1	c.197C>G	p.Ala66Gly	missense_variant	Exon 3 of 10	5		ENSP00000457096.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74208

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.080
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.77	.;P;.
Vest4		0.73
MutPred		0.44		.;Loss of catalytic residue at A66 (P = 0.0097);Loss of catalytic residue at A66 (P = 0.0097);
MVP		0.33
MPC		0.62
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs534115621; hg19: chr15-74174013;