3-100279714-T-C

Position:

• chr3-100279714-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001199198.3(TBC1D23):​c.119T>C​(p.Ile40Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,608,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: TBC1D23 NM_001199198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037118137).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000604 (92/152318) while in subpopulation NFE AF= 0.00107 (73/68018). AF 95% confidence interval is 0.000875. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	c.119T>C	p.Ile40Thr	missense_variant	2/19	ENST00000394144.9
TBC1D23	NM_018309.5	c.119T>C	p.Ile40Thr	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D23	ENST00000394144.9	c.119T>C	p.Ile40Thr	missense_variant	2/19	1	NM_001199198.3	P3

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000750 AC: 187 AN: 249214 Hom.: 0 AF XY: 0.000912 AC XY: 123 AN XY: 134834

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000856

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00105 AC: 1533 AN: 1456548 Hom.: 1 Cov.: 29 AF XY: 0.00102 AC XY: 738 AN XY: 724478

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000725

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000516

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74480

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000935 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The c.119T>C (p.I40T) alteration is located in exon 2 (coding exon 2) of the TBC1D23 gene. This alteration results from a T to C substitution at nucleotide position 119, causing the isoleucine (I) at amino acid position 40 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	.;.;T;T
Eigen	Benign	0.022
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.13	T;T;T;T
Sift4G	Uncertain	0.049	D;D;D;T
Polyphen		0.37, 0.26	.;B;B;.
Vest4		0.72, 0.71
MVP		0.38
MPC		0.31
ClinPred		0.013	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs148149385; hg19: chr3-99998558;