12-54962602-C-A

Position:

• chr12-54962602-C-A

Variant summary

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

The NM_001136030.3(TESPA1):​c.1296G>T​(p.Trp432Cys) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TESPA1 NM_001136030.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

TESPA1 (HGNC:29109): (thymocyte expressed, positive selection associated 1) Predicted to enable phospholipase binding activity. Predicted to be involved in several processes, including COP9 signalosome assembly; positive regulation of T cell differentiation in thymus; and positive regulation of T cell receptor signaling pathway. Predicted to act upstream of or within TCR signalosome assembly. Part of COP9 signalosome. [provided by Alliance of Genome Resources, Apr 2022]

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=0.1293653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TESPA1	NM_001136030.3	c.1296G>T	p.Trp432Cys	missense_variant	9/11	ENST00000449076.6	NP_001129502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TESPA1	ENST00000449076.6	c.1296G>T	p.Trp432Cys	missense_variant	9/11	2	NM_001136030.3	ENSP00000400892	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Dec 08, 2023

The c.1296G>T (p.W432C) alteration is located in exon 9 (coding exon 8) of the TESPA1 gene. This alteration results from a G to T substitution at nucleotide position 1296, causing the tryptophan (W) at amino acid position 432 to be replaced by a cysteine (C). 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	0.38
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.0033	.;.;.;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	.;T;.;.;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N;D;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.045	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.010	.;.;.;B;B;.
Vest4		0.39
MutPred		0.36		.;.;.;Gain of relative solvent accessibility (P = 0.025);Gain of relative solvent accessibility (P = 0.025);.;
MVP		0.17
MPC		0.36
ClinPred		0.63	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.22

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: rs1951156758; hg19: chr12-55356386;