NM_001308209.2:c.577G>A

Variant names:

• chr19-686990-C-T
• rs553412985
• NM_001308209.2:c.577G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001308209.2(PRSS57):​c.577G>A​(p.Gly193Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PRSS57 NM_001308209.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS57	NM_001308209.2	c.577G>A	p.Gly193Ser	missense_variant	Exon 4 of 5	ENST00000329267.9	NP_001295138.2
PRSS57	NM_214710.5	c.580G>A	p.Gly194Ser	missense_variant	Exon 4 of 5		NP_999875.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS57	ENST00000329267.9	c.577G>A	p.Gly193Ser	missense_variant	Exon 4 of 5	1	NM_001308209.2	ENSP00000327386.6
PRSS57	ENST00000613411.4	c.580G>A	p.Gly194Ser	missense_variant	Exon 4 of 5	1		ENSP00000482358.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727192

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.580G>A (p.G194S) alteration is located in exon 4 (coding exon 4) of the PRSS57 gene. This alteration results from a G to A substitution at nucleotide position 580, causing the glycine (G) at amino acid position 194 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.52	T
REVEL	Pathogenic	0.67
Sift4G	Benign	0.11	T;T
Polyphen		0.99	D;.
Vest4		0.61
MutPred		0.58		Loss of catalytic residue at G194 (P = 0.0391);.;
MVP		0.40
MPC		0.12
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.64
gMVP		0.53

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: rs553412985; hg19: chr19-686990;