chr12-54961249-C-T

Variant names:

• chr12-54961249-C-T
• rs997173
• NM_001136030.3:c.1486G>A

Variant summary

Our verdict is Benign. The variant received -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. 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. E496G) has been classified as Uncertain significance.

• 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
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136030.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TESPA1	NM_001136030.3	MANE Select	c.1486G>A	p.Glu496Lys	missense	Exon 10 of 11	NP_001129502.1	A2RU30-1
	TESPA1	NM_001098815.3		c.1486G>A	p.Glu496Lys	missense	Exon 10 of 11	NP_001092285.1	A2RU30-1
	TESPA1	NM_001351149.2		c.1486G>A	p.Glu496Lys	missense	Exon 11 of 12	NP_001338078.1	A2RU30-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TESPA1	ENST00000449076.6	TSL:2 MANE Select	c.1486G>A	p.Glu496Lys	missense	Exon 10 of 11	ENSP00000400892.1	A2RU30-1
	TESPA1	ENST00000316577.12	TSL:1	c.1486G>A	p.Glu496Lys	missense	Exon 10 of 11	ENSP00000312679.8	A2RU30-1
	TESPA1	ENST00000524622.5	TSL:1	c.1072G>A	p.Glu358Lys	missense	Exon 8 of 9	ENSP00000435622.1	A2RU30-2

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

GnomAD2 exomes AF: 0.194 AC: 48412 AN: 249554 AF XY: 0.203

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 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

African (AFR) AF: 0.0620 AC: 2075 AN: 33478

American (AMR) AF: 0.216 AC: 9650 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5409 AN: 26128

East Asian (EAS) AF: 0.629 AC: 24980 AN: 39696

South Asian (SAS) AF: 0.468 AC: 40383 AN: 86252

European-Finnish (FIN) AF: 0.0992 AC: 5295 AN: 53398

Middle Eastern (MID) AF: 0.202 AC: 1163 AN: 5764

European-Non Finnish (NFE) AF: 0.0621 AC: 69043 AN: 1111838

Other (OTH) AF: 0.150 AC: 9060 AN: 60366

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

African (AFR) AF: 0.0624 AC: 2589 AN: 41508

American (AMR) AF: 0.157 AC: 2404 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 720 AN: 3472

East Asian (EAS) AF: 0.633 AC: 3250 AN: 5138

South Asian (SAS) AF: 0.490 AC: 2359 AN: 4816

European-Finnish (FIN) AF: 0.0981 AC: 1039 AN: 10588

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.0652 AC: 4431 AN: 67996

Other (OTH) AF: 0.144 AC: 305 AN: 2114

Alfa AF: 0.0977 Hom.: 7075

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 v4.9

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
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.70
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.049
Sift	Benign	0.038	D
Sift4G	Benign	0.073	T
Polyphen		0.0040	B
Vest4		0.11
MPC		0.17
ClinPred		0.0054	T
GERP RS		2.3
Varity_R		0.057
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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