16-31135476-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002773.5(PRSS8):c.23G>A(p.Gly8Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,578,322 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (27 hom.)
• Consequence: PRSS8 NM_002773.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.536

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061965585).
• BP6: Variant 16-31135476-C-T is Benign according to our data. Variant chr16-31135476-C-T is described in ClinVar as [Benign]. Clinvar id is 771199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00403 (5753/1425994) while in subpopulation MID AF= 0.0295 (169/5722). AF 95% confidence interval is 0.0259. There are 27 homozygotes in gnomad4_exome. There are 2958 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS8	NM_002773.5	c.23G>A	p.Gly8Glu	missense_variant	1/6	ENST00000317508.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS8	ENST00000317508.11	c.23G>A	p.Gly8Glu	missense_variant	1/6	1	NM_002773.5	P1

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 611 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00474 AC: 880 AN: 185814 Hom.: 4 AF XY: 0.00486 AC XY: 489 AN XY: 100592

Gnomad AFR exome AF: 0.000407

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00178

Gnomad FIN exome AF: 0.000552

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00403 AC: 5753 AN: 1425994 Hom.: 27 Cov.: 31 AF XY: 0.00419 AC XY: 2958 AN XY: 706298

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00596

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.000790

Gnomad4 NFE exome AF: 0.00409

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00396 AC XY: 295 AN XY: 74480

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00575 Hom.: 4

Bravo AF: 0.00462

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000541 AC: 2

ESP6500EA AF: 0.00590 AC: 48

ExAC AF: 0.00359 AC: 427

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PRSS8: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.42	T;T;T;T
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.11	T;T;.;.
Polyphen		0.0060	B;.;.;.
Vest4		0.20
MVP		0.76
MPC		0.37
ClinPred		0.044	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.78

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: rs148529565; hg19: chr16-31146797;