12-54961249-C-T

Position:

• chr12-54961249-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001136030.3(TESPA1):​c.1486G>A​(p.Glu496Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,776 control chromosomes in the GnomAD database, including 25,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (2286 hom., cov: 32)
  • Exomes 𝑓: 0.11 (23299 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1057146E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TESPA1	NM_001136030.3	c.1486G>A	p.Glu496Lys	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>A	p.Glu496Lys	missense_variant	10/11	2	NM_001136030.3	ENSP00000400892.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17236 AN: 152018 Hom.: 2280 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.194 AC: 48412 AN: 249554 Hom.: 9257 AF XY: 0.203 AC XY: 27401 AN XY: 135250

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.649

Gnomad SAS exome AF: 0.476

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0704

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.114 AC: 167058 AN: 1461640 Hom.: 23299 Cov.: 33 AF XY: 0.125 AC XY: 90684 AN XY: 727098

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.0992

Gnomad4 NFE exome AF: 0.0621

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.113 AC: 17245 AN: 152136 Hom.: 2286 Cov.: 32 AF XY: 0.125 AC XY: 9279 AN XY: 74366

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.0981

Gnomad4 NFE AF: 0.0652

Gnomad4 OTH AF: 0.144

Alfa AF: 0.0980 Hom.: 3893

Bravo AF: 0.114

TwinsUK AF: 0.0655 AC: 243

ALSPAC AF: 0.0641 AC: 247

ESP6500AA AF: 0.0581 AC: 256

ESP6500EA AF: 0.0715 AC: 615

ExAC AF: 0.193 AC: 23409

Asia WGS AF: 0.481 AC: 1673 AN: 3478

EpiCase AF: 0.0797

EpiControl AF: 0.0824

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	.;.;T;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.70	.;.;.;T;T
MetaRNN	Benign	0.000011	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	.;.;L;L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.038	D;D;D;D;D
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.0040	.;.;B;B;.
Vest4		0.11
MPC		0.17
ClinPred		0.0054	T
GERP RS		2.3
Varity_R		0.057
gMVP		0.13

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: rs997173; hg19: chr12-55355033; COSMIC: COSV57259084; COSMIC: COSV57259084;