19-49880370-G-C

Variant names:

• chr19-49880370-G-C
• rs368116942
• NM_024682.3:c.287G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024682.3(TBC1D17):​c.287G>C​(p.Arg96Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBC1D17 NM_024682.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27038905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D17	NM_024682.3	c.287G>C	p.Arg96Pro	missense_variant	Exon 4 of 17	ENST00000221543.10	NP_078958.2
TBC1D17	NM_001168222.2	c.188G>C	p.Arg63Pro	missense_variant	Exon 3 of 16		NP_001161694.1
TBC1D17	XM_047439444.1	c.287G>C	p.Arg96Pro	missense_variant	Exon 4 of 16		XP_047295400.1
TBC1D17	XM_011527317.4	c.287G>C	p.Arg96Pro	missense_variant	Exon 4 of 14		XP_011525619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D17	ENST00000221543.10	c.287G>C	p.Arg96Pro	missense_variant	Exon 4 of 17	1	NM_024682.3	ENSP00000221543.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461568 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.19
Sift	Benign	0.15	T;T
Sift4G	Benign	0.061	T;T
Vest4		0.50
MutPred		0.36		Gain of glycosylation at S93 (P = 0.0635);.;
MVP		0.47
MPC		0.25
ClinPred		0.65	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.63
Mutation Taster		=59/41	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: rs368116942; hg19: chr19-50383627;