16-1241453-G-A

Position:

• chr16-1241453-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000338844.8(TPSAB1):​c.253G>A​(p.Ala85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 97,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (0 hom., cov: 22)
  • Exomes 𝑓: 0.23 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPSAB1 ENST00000338844.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58

Genes affected

TPSAB1 (HGNC:12019): (tryptase alpha/beta 1) Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3' UTR and contain tandem repeat sequences at the 5' flank and 3' UTR which are thought to play a role in regulation of the mRNA stability. These genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. The alleles of this gene exhibit an unusual amount of sequence variation, such that the alleles were once thought to represent two separate genes, alpha and beta 1. Beta tryptases appear to be the main isoenzymes expressed in mast cells; whereas in basophils, alpha tryptases predominate. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. [provided by RefSeq, Jul 2008]

TPSAB1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019491911).
• BP6: Variant 16-1241453-G-A is Benign according to our data. Variant chr16-1241453-G-A is described in ClinVar as [Benign]. Clinvar id is 1249015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSAB1	NM_003294.4	c.253G>A	p.Ala85Thr	missense_variant	4/6	ENST00000338844.8	NP_003285.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSAB1	ENST00000338844.8	c.253G>A	p.Ala85Thr	missense_variant	4/6	1	NM_003294.4	ENSP00000343577.3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 17203 AN: 97406 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.0865 AC: 10682 AN: 123512 Hom.: 1 AF XY: 0.0905 AC XY: 6008 AN XY: 66410

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0867

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.0982

Gnomad OTH exome AF: 0.0546

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.231 AC: 203717 AN: 883540 Hom.: 4 Cov.: 54 AF XY: 0.226 AC XY: 98745 AN XY: 436738

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.176 AC: 17204 AN: 97476 Hom.: 0 Cov.: 22 AF XY: 0.179 AC XY: 8526 AN XY: 47552

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.310

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.185

Alfa AF: 0.158 Hom.: 0

ExAC AF: 0.0692 AC: 8132

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.029
DANN	Benign	0.34
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.036	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.24
Sift	Benign	0.84	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0030	B;.
Vest4		0.041
MPC		1.6
ClinPred		0.0028	T
GERP RS		-5.6
Varity_R		0.090
gMVP		0.25

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: rs201351744; hg19: chr16-1291454; COSMIC: COSV58779797;