17-18636482-C-G

Variant names:

• chr17-18636482-C-G
• rs375857329
• NM_001039397.3:c.613G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039397.3(TBC1D28):​c.613G>C​(p.Gly205Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G205W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TBC1D28 NM_001039397.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.431
• Publications: 2 publications found

Genes affected

TBC1D28 (HGNC:26858): (TBC1 domain family member 28) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025896132).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039397.3. 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
	TBC1D28	NM_001039397.3	MANE Select	c.613G>C	p.Gly205Arg	missense	Exon 10 of 10	NP_001034486.2	Q2M2D7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D28	ENST00000405044.7	TSL:5 MANE Select	c.613G>C	p.Gly205Arg	missense	Exon 10 of 10	ENSP00000385821.1	Q2M2D7
	TBC1D28	ENST00000345096.8	TSL:2	c.613G>C	p.Gly205Arg	missense	Exon 9 of 9	ENSP00000339973.4	Q2M2D7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249326 AF XY: 0.0000370

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 FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.90
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.43
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.025	B
Vest4		0.060
MutPred		0.55		Gain of MoRF binding (P = 1e-04)
MVP		0.040
MPC		0.028
ClinPred		0.036	T
GERP RS		-1.2
Varity_R		0.19
gMVP		0.29
Mutation Taster		=98/2	polymorphism

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: rs375857329; hg19: chr17-18539795;