4-118338294-C-T

Position:

chr4-118338294-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003619.4(PRSS12):c.523G>A(p.Gly175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,920 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 15 hom. )

Consequence

PRSS12
NM_003619.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.09

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010552824).

BP6

Variant 4-118338294-C-T is Benign according to our data. Variant chr4-118338294-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211964.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS12	NM_003619.4 link	c.523G>A	p.Gly175Ser	missense_variant	2/13	ENST00000296498.3	NP_003610.2	P56730Q96I80
PRSS12	XM_011532387.3 link	c.523G>A	p.Gly175Ser	missense_variant	2/9		XP_011530689.1
PRSS12	XM_005263318.5 link	c.523G>A	p.Gly175Ser	missense_variant	2/10		XP_005263375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3 link	c.523G>A	p.Gly175Ser	missense_variant	2/13	1	NM_003619.4	ENSP00000296498.3		P56730

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

411

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00469

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00201

AC:

505

AN:

251002

Hom.:

AF XY:

0.00199

AC XY:

270

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00222

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00154

AC:

2249

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1182

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00508

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00257

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00139

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00270

AC:

411

AN:

152236

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00467

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00319

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00211

AC:

256

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 1

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PRSS12: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2015

- -

PRSS12-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.065

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

M_CAP

Benign

0.058

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.26

Sift

Benign

0.14

Sift4G

Benign

0.15

Polyphen

0.95

Vest4

0.46

MVP

0.70

MPC

0.54

ClinPred

0.036

GERP RS

4.5

Varity_R

0.25

gMVP

0.72

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