Genetic Variant TBC1D21:p.Arg246Ser (chr15-73886571-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_153356.3(TBC1D21):c.736C>A(p.Arg246Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R246C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TBC1D21
NM_153356.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Variant links:

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]

TBC1D21 links:

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ACMG classification

Classification made for transcript

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 link	c.736C>A	p.Arg246Ser	missense_variant	Exon 8 of 11	ENST00000300504.7	NP_699187.1	Q8IYX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D21	ENST00000300504.7 link	c.736C>A	p.Arg246Ser	missense_variant	Exon 8 of 11	1	NM_153356.3	ENSP00000300504.2	Q8IYX1-1
TBC1D21	ENST00000535547.6 link	c.628C>A	p.Arg210Ser	missense_variant	Exon 7 of 10	1		ENSP00000439325.2	Q8IYX1-2
TBC1D21	ENST00000562056.1 link	c.625C>A	p.Arg209Ser	missense_variant	Exon 7 of 10	5		ENSP00000457096.1	H3BTA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251420

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726988

show subpopulations

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:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736C>A (p.R246S) alteration is located in exon 8 (coding exon 8) of the TBC1D21 gene. This alteration results from a C to A substitution at nucleotide position 736, causing the arginine (R) at amino acid position 246 to be replaced by a serine (S). 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

0.39

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;.

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.043

D;D;D

Polyphen

0.25

.;B;.

Vest4

0.69

MutPred

0.71

.;Loss of catalytic residue at R246 (P = 0.0383);.;

MVP

0.41

MPC

0.60

ClinPred

0.49

GERP RS

3.0

Varity_R

0.62

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over