12-54963182-G-A

Position:

• chr12-54963182-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001136030.3(TESPA1):​c.716C>T​(p.Ser239Phe) 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: TESPA1 NM_001136030.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.59

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TESPA1	NM_001136030.3	c.716C>T	p.Ser239Phe	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.716C>T	p.Ser239Phe	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

Oct 05, 2023

The c.716C>T (p.S239F) alteration is located in exon 9 (coding exon 8) of the TESPA1 gene. This alteration results from a C to T substitution at nucleotide position 716, causing the serine (S) at amino acid position 239 to be replaced by a phenylalanine (F). 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;D;.
Vest4		0.95
MutPred		0.46		.;.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;
MVP		0.68
MPC		0.69
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1951199091; hg19: chr12-55356966; COSMIC: COSV57258523; COSMIC: COSV57258523;