rs754138689

Variant names:

• chr16-1256537-A-C
• rs754138689
• NM_012217.3:c.104A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-1256537-A-C
• chr16-1256537-A-G
• chr16-1256537-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012217.3(TPSD1):​c.104A>C​(p.Gln35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. Q35R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TPSD1 NM_012217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 0 publications found

Genes affected

TPSD1 (HGNC:14118): (tryptase delta 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. Although this gene may be an exception, most of the tryptase 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. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. This gene was once considered to be a pseudogene, although it is now believed to be a functional gene that encodes a protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10318023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012217.3. 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
	TPSD1	NM_012217.3	MANE Select	c.104A>C	p.Gln35Pro	missense	Exon 2 of 5	NP_036349.1	Q9BZJ3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPSD1	ENST00000211076.5	TSL:1 MANE Select	c.104A>C	p.Gln35Pro	missense	Exon 2 of 5	ENSP00000211076.3	Q9BZJ3-1
	TPSD1	ENST00000397534.6	TSL:5	c.83A>C	p.Gln28Pro	missense	Exon 3 of 6	ENSP00000380668.2	A0A0C4DFZ7
	TPSD1	ENST00000711393.1		c.104A>C	p.Gln35Pro	missense	Exon 2 of 5	ENSP00000518724.1	Q9BZJ3-2

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246376 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458198 Hom.: 0 Cov.: 99 AF XY: 0.00000138 AC XY: 1 AN XY: 725452

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4856

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111182

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 37

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.2
DANN	Benign	0.63
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Benign	0.27	T
Polyphen		0.44	B
Vest4		0.18
MutPred		0.36		Gain of glycosylation at T36 (P = 0.069)
MVP		0.34
MPC		0.019
ClinPred		0.11	T
GERP RS		-0.30
PromoterAI		0.013	Neutral
Varity_R		0.16
gMVP		0.89
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs754138689; hg19: chr16-1306538;