19-49882362-G-C

Variant names:

• chr19-49882362-G-C
• rs200460228
• NM_024682.3:c.760G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024682.3(TBC1D17):​c.760G>C​(p.Asp254His) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,609,412 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. 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. D254N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TBC1D17 NM_024682.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 3 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]

LOC124904743 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10319716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D17	NM_024682.3	c.760G>C	p.Asp254His	missense_variant	Exon 7 of 17	ENST00000221543.10	NP_078958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D17	ENST00000221543.10	c.760G>C	p.Asp254His	missense_variant	Exon 7 of 17	1	NM_024682.3	ENSP00000221543.4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.000479

GnomAD2 exomes AF: 0.0000444 AC: 11 AN: 247542 AF XY: 0.0000372

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1457172 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 725094

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111918

Other (OTH) AF: 0.0000828 AC: 5 AN: 60358

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74440

African (AFR) AF: 0.000289 AC: 12 AN: 41552

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760G>C (p.D254H) alteration is located in exon 7 (coding exon 7) of the TBC1D17 gene. This alteration results from a G to C substitution at nucleotide position 760, causing the aspartic acid (D) at amino acid position 254 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	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		4.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.071
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.037	D;D
Vest4		0.49
MVP		0.37
MPC		0.52
ClinPred		0.079	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.52
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200460228; hg19: chr19-50385619; COSMIC: COSV55577222; COSMIC: COSV55577222;