rs370770621

Variant names:

• chr19-685811-C-T
• rs370770621
• NM_001308209.2:c.754G>A

Variant summary

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

The NM_001308209.2(PRSS57):​c.754G>A​(p.Ala252Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,565,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PRSS57 NM_001308209.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.174
• Publications: 0 publications found

Genes affected

PRSS57 (HGNC:31397): (serine protease 57) This gene encodes an arginine-specific serine protease and member of the peptidase S1 family of proteins. The encoded protein may undergo proteolytic activation before storage in azurophil granules, in neutrophil cells of the immune system. Following neutrophil activation, the protease is released into the pericellular environment, where it may play a role in defense against microbial pathogens. [provided by RefSeq, Jul 2016]

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=0.10103613).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308209.2. 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
	PRSS57	NM_001308209.2	MANE Select	c.754G>A	p.Ala252Thr	missense	Exon 5 of 5	NP_001295138.2	A0A0A0MR61
	PRSS57	NM_214710.5		c.757G>A	p.Ala253Thr	missense	Exon 5 of 5	NP_999875.2	Q6UWY2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS57	ENST00000329267.9	TSL:1 MANE Select	c.754G>A	p.Ala252Thr	missense	Exon 5 of 5	ENSP00000327386.6	A0A0A0MR61
	PRSS57	ENST00000613411.4	TSL:1	c.757G>A	p.Ala253Thr	missense	Exon 5 of 5	ENSP00000482358.1	Q6UWY2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151944 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000171 AC: 3 AN: 175636 AF XY: 0.0000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 25 AN: 1413334 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 10 AN XY: 698328

African (AFR) AF: 0.0000309 AC: 1 AN: 32336

American (AMR) AF: 0.0000522 AC: 2 AN: 38308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 36880

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000193 AC: 21 AN: 1086588

Other (OTH) AF: 0.00 AC: 0 AN: 58454

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151944 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74192

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000484 AC: 2 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000148366), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.1
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.54	N
PhyloP100		-0.17
PrimateAI	Benign	0.39	T
REVEL	Benign	0.16
Sift4G	Benign	0.26	T
Polyphen		0.43	B
Vest4		0.31
MVP		0.29
MPC		0.017
ClinPred		0.030	T
GERP RS		1.5
Varity_R		0.13
gMVP		0.54
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs370770621; hg19: chr19-685811;