NM_153356.3:c.338G>A

Variant names:

• chr15-73884216-G-A
• rs16958445
• NM_153356.3:c.338G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153356.3(TBC1D21):​c.338G>A​(p.Arg113Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,184 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. R113W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (121 hom., cov: 32)
  • Exomes 𝑓: 0.017 (1233 hom.)
• Consequence: TBC1D21 NM_153356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015442073).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153356.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D21	NM_153356.3	MANE Select	c.338G>A	p.Arg113Gln	missense	Exon 4 of 11	NP_699187.1	Q8IYX1-1
	TBC1D21	NM_001286434.2		c.230G>A	p.Arg77Gln	missense	Exon 3 of 10	NP_001273363.1	Q8IYX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D21	ENST00000300504.7	TSL:1 MANE Select	c.338G>A	p.Arg113Gln	missense	Exon 4 of 11	ENSP00000300504.2	Q8IYX1-1
	TBC1D21	ENST00000535547.6	TSL:1	c.230G>A	p.Arg77Gln	missense	Exon 3 of 10	ENSP00000439325.2	Q8IYX1-2
	TBC1D21	ENST00000562056.1	TSL:5	c.338G>A	p.Arg113Gln	missense	Exon 4 of 10	ENSP00000457096.1	H3BTA9

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2264 AN: 152208 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0323 AC: 8128 AN: 251484 AF XY: 0.0360

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.0377

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00614

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0168 AC: 24545 AN: 1461858 Hom.: 1233 Cov.: 32 AF XY: 0.0197 AC XY: 14304 AN XY: 727242

African (AFR) AF: 0.00161 AC: 54 AN: 33480

American (AMR) AF: 0.00407 AC: 182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 955 AN: 26136

East Asian (EAS) AF: 0.149 AC: 5897 AN: 39698

South Asian (SAS) AF: 0.113 AC: 9738 AN: 86252

European-Finnish (FIN) AF: 0.0136 AC: 726 AN: 53420

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5768

European-Non Finnish (NFE) AF: 0.00461 AC: 5128 AN: 1111988

Other (OTH) AF: 0.0286 AC: 1725 AN: 60392

GnomAD4 genome AF: 0.0148 AC: 2257 AN: 152326 Hom.: 121 Cov.: 32 AF XY: 0.0178 AC XY: 1326 AN XY: 74490

African (AFR) AF: 0.00236 AC: 98 AN: 41574

American (AMR) AF: 0.00542 AC: 83 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.153 AC: 791 AN: 5180

South Asian (SAS) AF: 0.119 AC: 572 AN: 4824

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00600 AC: 408 AN: 68024

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0123 Hom.: 314

Bravo AF: 0.0124

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.0328 AC: 3988

Asia WGS AF: 0.151 AC: 525 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00717

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.28
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.024
Sift	Benign	0.26	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.12
MPC		0.28
ClinPred		0.0070	T
GERP RS		0.33
Varity_R		0.029
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16958445; hg19: chr15-74176557; COSMIC: COSV55994696;