chr19-49881457-G-A

Variant names:

• chr19-49881457-G-A
• rs779368014
• NM_024682.3:c.509G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024682.3(TBC1D17):​c.509G>A​(p.Arg170His) variant causes a missense change. The variant allele was found at a frequency of 0.0000373 in 1,609,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R170C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TBC1D17 NM_024682.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09775084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D17	NM_024682.3	c.509G>A	p.Arg170His	missense_variant	Exon 5 of 17	ENST00000221543.10	NP_078958.2
TBC1D17	NM_001168222.2	c.410G>A	p.Arg137His	missense_variant	Exon 4 of 16		NP_001161694.1
TBC1D17	XM_047439444.1	c.509G>A	p.Arg170His	missense_variant	Exon 5 of 16		XP_047295400.1
TBC1D17	XM_011527317.4	c.509G>A	p.Arg170His	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.509G>A	p.Arg170His	missense_variant	Exon 5 of 17	1	NM_024682.3	ENSP00000221543.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

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

GnomAD2 exomes AF: 0.0000691 AC: 17 AN: 245902 AF XY: 0.0000448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000364 AC: 53 AN: 1457224 Hom.: 0 Cov.: 32 AF XY: 0.0000359 AC XY: 26 AN XY: 725158

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111756

Other (OTH) AF: 0.0000332 AC: 2 AN: 60270

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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: 0.000217 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.509G>A (p.R170H) alteration is located in exon 5 (coding exon 5) of the TBC1D17 gene. This alteration results from a G to A substitution at nucleotide position 509, causing the arginine (R) at amino acid position 170 to be replaced by a histidine (H). 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	Benign	0.080
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.89	T
PhyloP100		4.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.043	D;D
Vest4		0.33
MutPred		0.38		Loss of MoRF binding (P = 0.0123);.;
MVP		0.43
MPC		0.41
ClinPred		0.72	D
GERP RS		5.5
gMVP		0.54
Mutation Taster		=85/15	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: rs779368014; hg19: chr19-50384714; COSMIC: COSV55577708; COSMIC: COSV55577708;