16-31132437-C-T

Variant names:

• chr16-31132437-C-T
• rs768072440
• NM_002773.5:c.697G>A

Variant summary

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

The NM_002773.5(PRSS8):​c.697G>A​(p.Ala233Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,382 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: PRSS8 NM_002773.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424

Genes affected

PRSS8 (HGNC:9491): (serine protease 8) This gene encodes a member of the peptidase S1 or chymotrypsin family of serine proteases. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate via a disulfide bond to form the heterodimeric enzyme. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. This protease exhibits trypsin-like substrate specificity, cleaving protein substrates at the carboxyl terminus of lysine or arginine residues. The encoded protease partially mediates proteolytic activation of the epithelial sodium channel, a regulator of sodium balance, and may also play a role in epithelial barrier formation. [provided by RefSeq, Feb 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, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS8	NM_002773.5	c.697G>A	p.Ala233Thr	missense_variant	Exon 5 of 6	ENST00000317508.11	NP_002764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS8	ENST00000317508.11	c.697G>A	p.Ala233Thr	missense_variant	Exon 5 of 6	1	NM_002773.5	ENSP00000319730.6
PRSS8	ENST00000568261.5	c.535G>A	p.Ala179Thr	missense_variant	Exon 5 of 6	2		ENSP00000457750.1
PRSS8	ENST00000567531.5	c.*2G>A		downstream_gene_variant		3		ENSP00000457673.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248752 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461382 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.697G>A (p.A233T) alteration is located in exon 5 (coding exon 5) of the PRSS8 gene. This alteration results from a G to A substitution at nucleotide position 697, causing the alanine (A) at amino acid position 233 to be replaced by a threonine (T). 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.52	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.060	T;T
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.80		Gain of ubiquitination at K231 (P = 0.143);.;
MVP		0.93
MPC		0.92
ClinPred		0.75	D
GERP RS		4.5
Varity_R		0.68
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs768072440; hg19: chr16-31143758; COSMIC: COSV54899080; COSMIC: COSV54899080;