16-1241317-G-C

Position:

• chr16-1241317-G-C

Variant summary

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

The NM_003294.4(TPSAB1):​c.226G>C​(p.Val76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 91,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.098 (0 hom., cov: 35)
  • Exomes 𝑓: 0.19 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPSAB1 NM_003294.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.937

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023636818).
• BP6: Variant 16-1241317-G-C is Benign according to our data. Variant chr16-1241317-G-C is described in ClinVar as [Benign]. Clinvar id is 1290457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSAB1	NM_003294.4	c.226G>C	p.Val76Leu	missense_variant	3/6	ENST00000338844.8	NP_003285.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSAB1	ENST00000338844.8	c.226G>C	p.Val76Leu	missense_variant	3/6	1	NM_003294.4	ENSP00000343577	P2

Frequencies

GnomAD3 genomes AF: 0.0979 AC: 8928 AN: 91218 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0776

Gnomad ASJ AF: 0.0895

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0954

GnomAD3 exomes AF: 0.0833 AC: 12194 AN: 146432 Hom.: 1 AF XY: 0.0853 AC XY: 6708 AN XY: 78636

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.0803

Gnomad EAS exome AF: 0.0970

Gnomad SAS exome AF: 0.0905

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.0701

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.190 AC: 152978 AN: 806064 Hom.: 4 Cov.: 162 AF XY: 0.184 AC XY: 73897 AN XY: 400850

Gnomad4 AFR exome AF: 0.0814

Gnomad4 AMR exome AF: 0.0732

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.0979 AC: 8936 AN: 91300 Hom.: 0 Cov.: 35 AF XY: 0.0990 AC XY: 4413 AN XY: 44584

Gnomad4 AFR AF: 0.0490

Gnomad4 AMR AF: 0.0776

Gnomad4 ASJ AF: 0.0895

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.102 Hom.: 0

ExAC AF: 0.187 AC: 22657

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.12
DANN	Benign	0.84
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.11	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.45	N;.;.
MutationTaster	Benign	0.70	P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.039
MutPred		0.66		Gain of catalytic residue at V76 (P = 0.0731);.;.;
MPC		0.063
ClinPred		0.0036	T
GERP RS		-3.0
Varity_R		0.17
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151324823; hg19: chr16-1291318; COSMIC: COSV58779760;