16-1221890-G-T

Position:

• chr16-1221890-G-T

Variant summary

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

The NM_012467.4(TPSG1):​c.864C>A​(p.Phe288Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 1,610,564 control chromosomes in the GnomAD database, including 213,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.55 (23373 hom., cov: 33)
  • Exomes 𝑓: 0.50 (189917 hom.)
• Consequence: TPSG1 NM_012467.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412

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]

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.528061E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPSG1	NM_012467.4	c.864C>A	p.Phe288Leu	missense_variant	6/6	ENST00000234798.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPSG1	ENST00000234798.5	c.864C>A	p.Phe288Leu	missense_variant	6/6	1	NM_012467.4	P1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82987 AN: 151868 Hom.: 23353 Cov.: 33

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.534

GnomAD3 exomes AF: 0.555 AC: 136801 AN: 246302 Hom.: 39770 AF XY: 0.543 AC XY: 72661 AN XY: 133860

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.681

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.872

Gnomad SAS exome AF: 0.472

Gnomad FIN exome AF: 0.613

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.503 AC: 733918 AN: 1458576 Hom.: 189917 Cov.: 60 AF XY: 0.500 AC XY: 363036 AN XY: 725364

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.886

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.606

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.513

GnomAD4 genome AF: 0.546 AC: 83042 AN: 151988 Hom.: 23373 Cov.: 33 AF XY: 0.556 AC XY: 41287 AN XY: 74274

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.614

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.541

Alfa AF: 0.487 Hom.: 32068

Bravo AF: 0.553

TwinsUK AF: 0.464 AC: 1722

ALSPAC AF: 0.493 AC: 1900

ESP6500AA AF: 0.592 AC: 2595

ESP6500EA AF: 0.478 AC: 4112

ExAC AF: 0.542 AC: 65514

Asia WGS AF: 0.674 AC: 2343 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.2
DANN	Benign	0.68
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.019
MutPred		0.47		Gain of helix (P = 0.0696);
MPC		0.0037
ClinPred		0.0020	T
GERP RS		2.5
gMVP		0.17

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: rs1004041; hg19: chr16-1271890; COSMIC: COSV52354812; COSMIC: COSV52354812;