rs13119545

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003619.4(PRSS12):c.164G>C(p.Arg55Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,532,850 control chromosomes in the GnomAD database, including 303,462 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 24460 hom., cov: 33)

Exomes 𝑓: 0.63 ( 279002 hom. )

Consequence

PRSS12
NM_003619.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0100

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=1.9058403E-6).

BP6

Variant 4-118352557-C-G is Benign according to our data. Variant chr4-118352557-C-G is described in ClinVar as [Benign]. Clinvar id is 130042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-118352557-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS12	NM_003619.4 linkuse as main transcript	c.164G>C	p.Arg55Thr	missense_variant	1/13	ENST00000296498.3	NP_003610.2	P56730Q96I80
PRSS12	XM_011532387.3 linkuse as main transcript	c.164G>C	p.Arg55Thr	missense_variant	1/9		XP_011530689.1
PRSS12	XM_005263318.5 linkuse as main transcript	c.164G>C	p.Arg55Thr	missense_variant	1/10		XP_005263375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3 linkuse as main transcript	c.164G>C	p.Arg55Thr	missense_variant	1/13	1	NM_003619.4	ENSP00000296498.3		P56730

Frequencies

GnomAD3 genomes

AF:

0.541

AC:

81951

AN:

151352

Hom.:

24455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.633

Gnomad AMR

AF:

0.716

Gnomad ASJ

AF:

0.737

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.554

Gnomad FIN

AF:

0.542

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.653

Gnomad OTH

AF:

0.582

GnomAD3 exomes

AF:

0.616

AC:

93306

AN:

151440

Hom.:

29971

AF XY:

0.614

AC XY:

50499

AN XY:

82292

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.734

Gnomad EAS exome

AF:

0.469

Gnomad SAS exome

AF:

0.550

Gnomad FIN exome

AF:

0.549

Gnomad NFE exome

AF:

0.652

Gnomad OTH exome

AF:

0.649

GnomAD4 exome

AF:

0.630

AC:

870633

AN:

1381390

Hom.:

279002

Cov.:

AF XY:

0.629

AC XY:

429071

AN XY:

681878

show subpopulations

Gnomad4 AFR exome

AF:

0.271

Gnomad4 AMR exome

AF:

0.744

Gnomad4 ASJ exome

AF:

0.740

Gnomad4 EAS exome

AF:

0.428

Gnomad4 SAS exome

AF:

0.551

Gnomad4 FIN exome

AF:

0.557

Gnomad4 NFE exome

AF:

0.650

Gnomad4 OTH exome

AF:

0.620

GnomAD4 genome

AF:

0.541

AC:

81964

AN:

151460

Hom.:

24460

Cov.:

AF XY:

0.539

AC XY:

39922

AN XY:

74038

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.716

Gnomad4 ASJ

AF:

0.737

Gnomad4 EAS

AF:

0.468

Gnomad4 SAS

AF:

0.553

Gnomad4 FIN

AF:

0.542

Gnomad4 NFE

AF:

0.653

Gnomad4 OTH

AF:

0.578

Alfa

AF:

0.605

Hom.:

7232

Bravo

AF:

0.547

TwinsUK

AF:

0.655

AC:

2427

ALSPAC

AF:

0.667

AC:

2570

ESP6500AA

AF:

0.324

AC:

1352

ESP6500EA

AF:

0.665

AC:

5475

ExAC

AF:

0.532

AC:

58065

Asia WGS

AF:

0.513

AC:

1750

AN:

3414

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2013	- -

Intellectual disability, autosomal recessive 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.1

DANN

Benign

0.81

DEOGEN2

Benign

0.047

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0000019

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.14

REVEL

Benign

0.074

Sift

Benign

0.13

Sift4G

Benign

0.075

Polyphen

0.020

Vest4

0.10

MPC

0.41

ClinPred

0.0036

GERP RS

1.3

Varity_R

0.094

gMVP

0.23

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