16-1221910-G-T

Position:

• chr16-1221910-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012467.4(TPSG1):​c.844C>A​(p.Leu282Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,611,486 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: TPSG1 NM_012467.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.175

Genes affected

TPSG1 (HGNC:14134): (tryptase gamma 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. There is uncertainty regarding the number of genes in this cluster. Currently four functional genes - alpha I, beta I, beta II and gamma I - have been identified. And beta I has an allelic variant named alpha II, beta II has an allelic variant beta III, also gamma I has an allelic variant gamma II. Beta tryptases appear to be the main isoenzymes expressed in mast cells; whereas in basophils, alpha-tryptases predominant. This gene differs from other members of the tryptase gene family in that it has C-terminal hydrophobic domain, which may serve as a membrane anchor. 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046982765).
• BP6: Variant 16-1221910-G-T is Benign according to our data. Variant chr16-1221910-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 713528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSG1	NM_012467.4	c.844C>A	p.Leu282Ile	missense_variant	6/6	ENST00000234798.5	NP_036599.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSG1	ENST00000234798.5	c.844C>A	p.Leu282Ile	missense_variant	6/6	1	NM_012467.4	ENSP00000234798.4

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152176 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00246 AC: 608 AN: 247206 Hom.: 1 AF XY: 0.00259 AC XY: 348 AN XY: 134340

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000494

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00425 AC: 6199 AN: 1459192 Hom.: 18 Cov.: 72 AF XY: 0.00406 AC XY: 2945 AN XY: 725714

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000976

Gnomad4 FIN exome AF: 0.000441

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152294 Hom.: 1 Cov.: 34 AF XY: 0.00250 AC XY: 186 AN XY: 74458

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00395 Hom.: 2

Bravo AF: 0.00267

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00238 AC: 288

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00529

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.0
DANN	Benign	0.97
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.086
Sift	Benign	0.56	T
Sift4G	Benign	0.44	T
Vest4		0.087
MVP		0.30
MPC		0.0054
ClinPred		0.00059	T
GERP RS		-1.0
gMVP		0.16

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: rs117001332; hg19: chr16-1271910;