Variant 3-100281746-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_001199198.3(TBC1D23):c.170C>T(p.Ala57Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TBC1D23
NM_001199198.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000894 (13/1454474) while in subpopulation MID AF= 0.00191 (11/5746). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D23	NM_001199198.3 linkuse as main transcript	c.170C>T	p.Ala57Val	missense_variant	3/19	ENST00000394144.9
TBC1D23	NM_018309.5 linkuse as main transcript	c.170C>T	p.Ala57Val	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D23	ENST00000394144.9 linkuse as main transcript	c.170C>T	p.Ala57Val	missense_variant	3/19	1	NM_001199198.3	P3	Q9NUY8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000894

AC:

AN:

1454474

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 05, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.038

.;.;T;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.39

T;D;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

.;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.059

T;D;D;T

Polyphen

0.97, 0.98

.;D;D;.

Vest4

0.89, 0.89

MutPred

0.50

.;Gain of MoRF binding (P = 0.1095);Gain of MoRF binding (P = 0.1095);.;

MVP

0.44

MPC

0.56

ClinPred

0.97

GERP RS

5.3

Varity_R

0.54

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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