rs77322543

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003619.4(PRSS12):c.1270G>A(p.Val424Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,613,994 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V424V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0052 ( 14 hom., cov: 31)

Exomes 𝑓: 0.00049 ( 2 hom. )

Consequence

PRSS12
NM_003619.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

PRSS12 (HGNC:9477): (serine protease 12) This gene encodes a member of the trypsin family of serine proteases and contains a signal peptide, a proline-rich region, a Kringle domain, four scavenger receptor cysteine-rich domains, and a trypsin-like serine protease domain. The protein, sometimes referred to as neurotrypsin or motopsin, is secreted from neuronal cells and localizes to the synaptic cleft. Studies in mice show that this protein cleaves a protein, agrin, that is important for the formation and maintenance of exitatory synapses. Defects in this gene cause a form of autosomal recessive cognitive impairment (MRT1). [provided by RefSeq, Jul 2017]

PRSS12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01632011).

BP6

Variant 4-118316204-C-T is Benign according to our data. Variant chr4-118316204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (797/152158) while in subpopulation AFR AF= 0.0182 (754/41500). AF 95% confidence interval is 0.0171. There are 14 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS12	NM_003619.4 link	c.1270G>A	p.Val424Ile	missense_variant	Exon 6 of 13	ENST00000296498.3	NP_003610.2	P56730Q96I80
PRSS12	XM_011532387.3 link	c.1270G>A	p.Val424Ile	missense_variant	Exon 6 of 9		XP_011530689.1
PRSS12	XM_005263318.5 link	c.1270G>A	p.Val424Ile	missense_variant	Exon 6 of 10		XP_005263375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3 link	c.1270G>A	p.Val424Ile	missense_variant	Exon 6 of 13	1	NM_003619.4	ENSP00000296498.3		P56730
PRSS12	ENST00000503043.1 link	n.298G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

796

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00133

AC:

335

AN:

251284

Hom.:

AF XY:

0.000957

AC XY:

130

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.000723

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000488

AC:

713

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

306

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0182

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.00524

AC:

797

AN:

152158

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

364

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0182

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000832

Hom.:

Bravo

AF:

0.00585

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.92

REVEL

Benign

0.22

Sift

Benign

0.19

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.30

MVP

0.61

MPC

0.58

ClinPred

0.058

GERP RS

6.2

Varity_R

0.11

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over