19-49881445-G-T

Variant names:

• chr19-49881445-G-T
• rs573671420
• NM_024682.3:c.497G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024682.3(TBC1D17):​c.497G>T​(p.Arg166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R166C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TBC1D17 NM_024682.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.933
• Publications: 1 publications found

Genes affected

TBC1D17 (HGNC:25699): (TBC1 domain family member 17) Predicted to enable GTPase activator activity. Involved in retrograde transport, endosome to Golgi. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D17	NM_024682.3	c.497G>T	p.Arg166Leu	missense_variant	Exon 5 of 17	ENST00000221543.10	NP_078958.2
TBC1D17	NM_001168222.2	c.398G>T	p.Arg133Leu	missense_variant	Exon 4 of 16		NP_001161694.1
TBC1D17	XM_047439444.1	c.497G>T	p.Arg166Leu	missense_variant	Exon 5 of 16		XP_047295400.1
TBC1D17	XM_011527317.4	c.497G>T	p.Arg166Leu	missense_variant	Exon 5 of 14		XP_011525619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D17	ENST00000221543.10	c.497G>T	p.Arg166Leu	missense_variant	Exon 5 of 17	1	NM_024682.3	ENSP00000221543.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.0087	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.98	T
PhyloP100		0.93
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.10
Sift	Benign	0.060	T;T
Sift4G	Benign	0.15	T;T
Vest4		0.65
MutPred		0.46		Loss of MoRF binding (P = 0.001);.;
MVP		0.42
MPC		0.21
ClinPred		0.94	D
GERP RS		5.6
gMVP		0.66
Mutation Taster		=87/13	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: rs573671420; hg19: chr19-50384702;