rs534115621

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-73881672-C-A
• chr15-73881672-C-G
• chr15-73881672-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153356.3(TBC1D21):​c.197C>A​(p.Ala66Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D21	NM_153356.3	c.197C>A	p.Ala66Asp	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>A	p.Ala66Asp	missense_variant	Exon 3 of 11	1	NM_153356.3	ENSP00000300504.2
TBC1D21	ENST00000535547.6	c.89C>A	p.Ala30Asp	missense_variant	Exon 2 of 10	1		ENSP00000439325.2
TBC1D21	ENST00000562056.1	c.197C>A	p.Ala66Asp	missense_variant	Exon 3 of 10	5		ENSP00000457096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;D;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.92	.;P;.
Vest4		0.90
MutPred		0.59		.;Loss of catalytic residue at A66 (P = 0.0479);Loss of catalytic residue at A66 (P = 0.0479);
MVP		0.37
MPC		0.96
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.80
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74174013;