Variant 3-17185109-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001349074.2(TBC1D5):c.1918G>C(p.Val640Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00238 in 1,609,998 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 5 hom. )

Consequence

TBC1D5
NM_001349074.2 missense, splice_region

Scores

Splicing: ADA: 0.9984

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.59

Variant links:

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]

TBC1D5 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 3-17185109-C-G is Benign according to our data. Variant chr3-17185109-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3056326.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 linkuse as main transcript	c.1918G>C	p.Val640Leu	missense_variant, splice_region_variant	20/23	ENST00000696125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D5	ENST00000696125.1 linkuse as main transcript	c.1918G>C	p.Val640Leu	missense_variant, splice_region_variant	20/23		NM_001349074.2	P2	Q92609-2
	ENST00000649558.1 linkuse as main transcript	n.699-18614C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00403

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00194

AC:

486

AN:

250796

Hom.:

AF XY:

0.00188

AC XY:

255

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000581

Gnomad ASJ exome

AF:

0.000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00239

AC:

3482

AN:

1457752

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1733

AN XY:

725146

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00123

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.00336

Gnomad4 NFE exome

AF:

0.00270

Gnomad4 OTH exome

AF:

0.00203

GnomAD4 genome

AF:

0.00230

AC:

350

AN:

152246

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00293

Gnomad4 NFE

AF:

0.00403

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00307

Hom.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00201

AC:

244

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TBC1D5-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2022

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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.32

M_CAP

Benign

0.021

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.60

D;D;D;N

PROVEAN

Benign

-0.54

REVEL

Benign

0.21

Sift

Uncertain

0.020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.35

MVP

0.74

ClinPred

0.021

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: 19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over