NM_001039397.3:c.206G>T

Variant names:

• chr17-18638694-C-A
• rs779017445
• NM_001039397.3:c.206G>T

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.206G>T​(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R69H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TBC1D28 NM_001039397.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.977
• Publications: 1 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]

ENSG00000287058 (HGNC:):

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=0.065588176).

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.206G>T	p.Arg69Leu	missense	Exon 7 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.206G>T	p.Arg69Leu	missense	Exon 7 of 10	ENSP00000385821.1	Q2M2D7
	TBC1D28	ENST00000345096.8	TSL:2	c.206G>T	p.Arg69Leu	missense	Exon 6 of 9	ENSP00000339973.4	Q2M2D7
	ENSG00000287058	ENST00000570881.1	TSL:5	n.*167G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461694 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.0000331 AC: 2 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.58
DANN	Benign	0.89
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L
PhyloP100		-0.98
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.0050
Sift	Benign	0.16	T
Sift4G	Benign	0.13	T
Polyphen		0.10	B
Vest4		0.11
MutPred		0.39		Loss of helix (P = 0.0558)
MVP		0.040
MPC		0.49
ClinPred		0.052	T
GERP RS		-1.9
Varity_R		0.073
gMVP		0.078
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779017445; hg19: chr17-18542007; COSMIC: COSV108865764; COSMIC: COSV108865764;