chr3-100281746-C-T

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

3
9
7

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]

Genome browser will be placed here

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
TBC1D23NM_001199198.3 linkuse as main transcriptc.170C>T p.Ala57Val missense_variant 3/19 ENST00000394144.9
TBC1D23NM_018309.5 linkuse as main transcriptc.170C>T p.Ala57Val missense_variant 3/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TBC1D23ENST00000394144.9 linkuse as main transcriptc.170C>T p.Ala57Val missense_variant 3/191 NM_001199198.3 P3Q9NUY8-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000894
AC:
13
AN:
1454474
Hom.:
0
Cov.:
28
AF XY:
0.00000967
AC XY:
7
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.:
33
Alfa
AF:
0.0000468
Hom.:
0

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 submitterclinical testingBaylor GeneticsMay 05, 2020This 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
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.038
.;.;T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.39
T;D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.57
D;D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.3
.;M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.80
T
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
D
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.

Other links and lift over

dbSNP: rs1007913441; hg19: chr3-100000590; API