17-18638696-T-A

Position:

• chr17-18638696-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039397.3(TBC1D28):​c.204A>T​(p.Arg68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TBC1D28 NM_001039397.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.16

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06221518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D28	NM_001039397.3	c.204A>T	p.Arg68Ser	missense_variant	7/10	ENST00000405044.7	NP_001034486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D28	ENST00000405044.7	c.204A>T	p.Arg68Ser	missense_variant	7/10	5	NM_001039397.3	ENSP00000385821.1
TBC1D28	ENST00000345096.8	c.204A>T	p.Arg68Ser	missense_variant	6/9	2		ENSP00000339973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461694 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727156

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.204A>T (p.R68S) alteration is located in exon 7 (coding exon 4) of the TBC1D28 gene. This alteration results from a A to T substitution at nucleotide position 204, causing the arginine (R) at amino acid position 68 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	0.35
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.3
DANN	Benign	0.87
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.010
Sift	Benign	0.15	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.11	B;B
Vest4		0.081
MutPred		0.42		Gain of phosphorylation at R68 (P = 0.0247);Gain of phosphorylation at R68 (P = 0.0247);
MVP		0.061
MPC		0.46
ClinPred		0.070	T
GERP RS		-0.32
Varity_R		0.13
gMVP		0.090

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

LitVar

Other links and lift over

dbSNP: rs2031628038; hg19: chr17-18542009;