3-100261059-G-A

Position:

• chr3-100261059-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199198.3(TBC1D23):​c.41G>A​(p.Ser14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D23 NM_001199198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09151149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D23	NM_001199198.3	c.41G>A	p.Ser14Asn	missense_variant	1/19	ENST00000394144.9	NP_001186127.1
TBC1D23	NM_018309.5	c.41G>A	p.Ser14Asn	missense_variant	1/18		NP_060779.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D23	ENST00000394144.9	c.41G>A	p.Ser14Asn	missense_variant	1/19	1	NM_001199198.3	ENSP00000377700.4
TBC1D23	ENST00000344949.9	c.41G>A	p.Ser14Asn	missense_variant	1/18	1		ENSP00000340693.5
TBC1D23	ENST00000485687.5	c.41G>A	p.Ser14Asn	missense_variant	1/5	3		ENSP00000417487.1
TBC1D23	ENST00000486274.5	n.-5G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Sep 11, 2024

The c.41G>A (p.S14N) alteration is located in exon 1 (coding exon 1) of the TBC1D23 gene. This alteration results from a G to A substitution at nucleotide position 41, causing the serine (S) at amino acid position 14 to be replaced by an asparagine (N). 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	Benign	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.024	.;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.13	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0030, 0.0060	.;B;B
Vest4		0.32, 0.35
MutPred		0.25		Loss of glycosylation at S14 (P = 0.0076);Loss of glycosylation at S14 (P = 0.0076);Loss of glycosylation at S14 (P = 0.0076);
MVP		0.26
MPC		0.24
ClinPred		0.44	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-99979903;