12-54961249-C-G

Position:

• chr12-54961249-C-G

Variant summary

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

The NM_001136030.3(TESPA1):​c.1486G>C​(p.Glu496Gln) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E496K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TESPA1 NM_001136030.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.705

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=0.090660125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TESPA1	NM_001136030.3	c.1486G>C	p.Glu496Gln	missense_variant	10/11	ENST00000449076.6	NP_001129502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TESPA1	ENST00000449076.6	c.1486G>C	p.Glu496Gln	missense_variant	10/11	2	NM_001136030.3	ENSP00000400892	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	.;.;T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.61	.;.;.;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.091	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	.;.;L;L;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.072
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Benign	0.072	T;T;T;T;T
Polyphen		0.83	.;.;P;P;.
Vest4		0.13
MutPred		0.12		.;.;Gain of MoRF binding (P = 0.1072);Gain of MoRF binding (P = 0.1072);.;
MVP		0.39
MPC		0.16
ClinPred		0.43	T
GERP RS		2.3
Varity_R		0.074
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs997173; hg19: chr12-55355033;