chr3-17258593-T-TA

Position:

• chr3-17258593-T-TA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001349074.2(TBC1D5):​c.1246-3_1246-2insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,573,312 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: TBC1D5 NM_001349074.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49

Genes affected

TBC1D5 (HGNC:19166): (TBC1 domain family member 5) Enables AP-2 adaptor complex binding activity and retromer complex binding activity. Involved in several processes, including macroautophagy; positive regulation of receptor internalization; and retrograde transport, endosome to Golgi. Located in Golgi apparatus; autophagosome; and endosome membrane. Part of retromer complex. Colocalizes with AP-2 adaptor complex and Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 3-17258593-T-TA is Benign according to our data. Variant chr3-17258593-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 3041409.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D5	NM_001349074.2	c.1246-3_1246-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000696125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D5	ENST00000696125.1	c.1246-3_1246-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001349074.2	P2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 213 AN: 150934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000778

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00214

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.00252 AC: 3590 AN: 1422262 Hom.: 5 Cov.: 29 AF XY: 0.00242 AC XY: 1715 AN XY: 707938

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.000315

Gnomad4 EAS exome AF: 0.000235

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.000696

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00141 AC: 213 AN: 151050 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 90 AN XY: 73772

Gnomad4 AFR AF: 0.000800

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000194

Gnomad4 NFE AF: 0.00214

Gnomad4 OTH AF: 0.00144

Bravo AF: 0.00150

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TBC1D5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs546735695; hg19: chr3-17300085;