rs368896872

Variant names:

• chr19-691859-C-A
• rs368896872
• NM_001308209.2:c.377G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-691859-C-A
• chr19-691859-C-T

Variant summary

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

The NM_001308209.2(PRSS57):​c.377G>T​(p.Arg126Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000849 in 1,177,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R126Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: PRSS57 NM_001308209.2 missense, splice_region
• Scores: Splicing: ADA: 0.0008788
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.572
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.377G>T	p.Arg126Leu	missense splice_region	Exon 3 of 5	NP_001295138.2	A0A0A0MR61
	PRSS57	NM_214710.5		c.380G>T	p.Arg127Leu	missense splice_region	Exon 3 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.377G>T	p.Arg126Leu	missense splice_region	Exon 3 of 5	ENSP00000327386.6	A0A0A0MR61
	PRSS57	ENST00000613411.4	TSL:1	c.380G>T	p.Arg127Leu	missense splice_region	Exon 3 of 5	ENSP00000482358.1	Q6UWY2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.49e-7 AC: 1 AN: 1177576 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 566340

⚠️ 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: 25030

American (AMR) AF: 0.00 AC: 0 AN: 17696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15620

East Asian (EAS) AF: 0.00 AC: 0 AN: 30602

South Asian (SAS) AF: 0.00 AC: 0 AN: 32498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4668

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 962188

Other (OTH) AF: 0.00 AC: 0 AN: 47114

⚠️ 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	Benign	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.57
PrimateAI	Benign	0.29	T
REVEL	Uncertain	0.52
Sift4G	Uncertain	0.010	D
Polyphen		0.64	P
Vest4		0.24
MutPred		0.69		Loss of sheet (P = 0.1501)
MVP		0.24
MPC		0.016
ClinPred		0.86	D
GERP RS		-0.28
Varity_R		0.56
gMVP		0.50
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.010		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: rs368896872; hg19: chr19-691859; COSMIC: COSV100249567; COSMIC: COSV100249567;