chr3-100279687-G-C

Position:

chr3-100279687-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199198.3(TBC1D23):c.92G>C(p.Cys31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00572 in 1,608,862 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 34 hom. )

Consequence

TBC1D23
NM_001199198.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.31

Variant links:

Genes affected

TBC1D23 (HGNC:25622): (TBC1 domain family member 23) Involved in brain development; retrograde transport, endosome to Golgi; and vesicle tethering to Golgi. Located in cytoplasmic vesicle and trans-Golgi network. Colocalizes with WASH complex. Implicated in pontocerebellar hypoplasia. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008267939).

BP6

Variant 3-100279687-G-C is Benign according to our data. Variant chr3-100279687-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 801991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00467 (711/152322) while in subpopulation NFE AF= 0.00635 (432/68034). AF 95% confidence interval is 0.00586. There are 2 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D23	NM_001199198.3 linkuse as main transcript	c.92G>C	p.Cys31Ser	missense_variant	2/19	ENST00000394144.9
TBC1D23	NM_018309.5 linkuse as main transcript	c.92G>C	p.Cys31Ser	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D23	ENST00000394144.9 linkuse as main transcript	c.92G>C	p.Cys31Ser	missense_variant	2/19	1	NM_001199198.3	P3	Q9NUY8-1

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

710

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00512

AC:

1277

AN:

249318

Hom.:

AF XY:

0.00556

AC XY:

750

AN XY:

134854

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.0256

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00694

Gnomad FIN exome

AF:

0.00195

Gnomad NFE exome

AF:

0.00555

Gnomad OTH exome

AF:

0.00606

GnomAD4 exome

AF:

0.00583

AC:

8495

AN:

1456540

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

4239

AN XY:

724494

show subpopulations

Gnomad4 AFR exome

AF:

0.000869

Gnomad4 AMR exome

AF:

0.00336

Gnomad4 ASJ exome

AF:

0.0274

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00648

Gnomad4 FIN exome

AF:

0.00220

Gnomad4 NFE exome

AF:

0.00587

Gnomad4 OTH exome

AF:

0.00649

GnomAD4 genome

AF:

0.00467

AC:

711

AN:

152322

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.0317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.00635

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00685

Hom.:

Bravo

AF:

0.00491

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00503

AC:

611

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TBC1D23: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 11, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Pontocerebellar hypoplasia, type 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.22

.;.;T;T

Eigen

Benign

0.084

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.4

D;D;D;D

REVEL

Benign

0.18

Sift

Benign

0.045

D;T;T;D

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.084, 0.051

.;B;B;.

Vest4

0.24, 0.24

MutPred

0.41

Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);.;

MVP

0.46

MPC

0.36

ClinPred

0.050

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.47

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

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