chr19-685864-G-C

Variant names:

• chr19-685864-G-C
• rs372449854
• NM_001308209.2:c.701C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001308209.2(PRSS57):​c.701C>G​(p.Ser234Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000711 in 1,405,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S234L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PRSS57 NM_001308209.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

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.701C>G	p.Ser234Trp	missense	Exon 5 of 5	NP_001295138.2	A0A0A0MR61
	PRSS57	NM_214710.5		c.704C>G	p.Ser235Trp	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.701C>G	p.Ser234Trp	missense	Exon 5 of 5	ENSP00000327386.6	A0A0A0MR61
	PRSS57	ENST00000613411.4	TSL:1	c.704C>G	p.Ser235Trp	missense	Exon 5 of 5	ENSP00000482358.1	Q6UWY2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1405828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 694262

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

African (AFR) AF: 0.00 AC: 0 AN: 32046

American (AMR) AF: 0.00 AC: 0 AN: 36848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 36422

South Asian (SAS) AF: 0.00 AC: 0 AN: 79800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083414

Other (OTH) AF: 0.00 AC: 0 AN: 58290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.69	N
PhyloP100		4.0
PrimateAI	Uncertain	0.70	T
REVEL	Pathogenic	0.79
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.83		Loss of glycosylation at S235 (P = 0.0384)
MVP		0.39
MPC		0.12
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.76
gMVP		0.79
Mutation Taster		=61/39	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: rs372449854; hg19: chr19-685864;