18-36800225-A-T

Position:

• chr18-36800225-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015476.4(TPGS2):​c.469T>A​(p.Cys157Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPGS2 NM_015476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53

Genes affected

TPGS2 (HGNC:24561): (tubulin polyglutamylase complex subunit 2) This gene encodes a protein that is a component of the neuronal polyglutamylase complex, which plays a role in post-translational addition of glutamate residues to C-terminal tubulin tails. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPGS2	NM_015476.4	c.469T>A	p.Cys157Ser	missense_variant	5/7	ENST00000334295.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPGS2	ENST00000334295.9	c.469T>A	p.Cys157Ser	missense_variant	5/7	1	NM_015476.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.469T>A (p.C157S) alteration is located in exon 5 (coding exon 5) of the TPGS2 gene. This alteration results from a T to A substitution at nucleotide position 469, causing the cysteine (C) at amino acid position 157 to be replaced by a serine (S). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;.;D
Polyphen		1.0, 1.0, 0.99	.;.;.;D;.;D;.;D
Vest4		0.93
MutPred		0.71		Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);.;.;.;Gain of disorder (P = 0.002);
MVP		0.70
MPC		0.24
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1019256718; hg19: chr18-34380188;