dbSNP rs760609916: TBC1D21:p.Thr71Arg (chr15-73881687-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_153356.3(TBC1D21):c.212C>G(p.Thr71Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,756 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. T71M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBC1D21
NM_153356.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.70

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D21	NM_153356.3 link	c.212C>G	p.Thr71Arg	missense_variant	Exon 3 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.212C>G	p.Thr71Arg	missense_variant	Exon 3 of 11	1	NM_153356.3	ENSP00000300504.2	Q8IYX1-1
TBC1D21	ENST00000535547.6 link	c.104C>G	p.Thr35Arg	missense_variant	Exon 2 of 10	1		ENSP00000439325.2	Q8IYX1-2
TBC1D21	ENST00000562056.1 link	c.212C>G	p.Thr71Arg	missense_variant	Exon 3 of 10	5		ENSP00000457096.1	H3BTA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251222

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727178

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

.;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.88

MutPred

0.72

.;Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);

MVP

0.42

MPC

0.93

ClinPred

0.85

GERP RS

4.9

Varity_R

0.44

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: -43

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over