chr4-118352557-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRSS12	NM_003619.4 link	c.164G>C	p.Arg55Thr	missense_variant	Exon 1 of 13	ENST00000296498.3	NP_003610.2	P56730Q96I80
PRSS12	NM_001440549.1 link	c.164G>C	p.Arg55Thr	missense_variant	Exon 1 of 13
PRSS12	NM_001440550.1 link	c.164G>C	p.Arg55Thr	missense_variant	Exon 1 of 9
PRSS12	NM_001440551.1 link	c.164G>C	p.Arg55Thr	missense_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3 link	c.164G>C	p.Arg55Thr	missense_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.616

AC:

93306

AN:

151440

AF XY:

0.614

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 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

African (AFR)

AF:

0.271

AC:

8011

AN:

29596

American (AMR)

AF:

0.744

AC:

24974

AN:

33552

Ashkenazi Jewish (ASJ)

AF:

0.740

AC:

17876

AN:

24150

East Asian (EAS)

AF:

0.428

AC:

14448

AN:

33774

South Asian (SAS)

AF:

0.551

AC:

42919

AN:

77910

European-Finnish (FIN)

AF:

0.557

AC:

27228

AN:

48888

Middle Eastern (MID)

AF:

0.613

AC:

3396

AN:

5540

European-Non Finnish (NFE)

AF:

0.650

AC:

696457

AN:

1070996

Other (OTH)

AF:

0.620

AC:

35324

AN:

56984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

17950

35901

53851

71802

89752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.541

AC:

81964

AN:

151460

Hom.:

24460

Cov.:

AF XY:

0.539

AC XY:

39922

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.280

AC:

11593

AN:

41420

American (AMR)

AF:

0.716

AC:

10915

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

2548

AN:

3458

East Asian (EAS)

AF:

0.468

AC:

2382

AN:

5090

South Asian (SAS)

AF:

0.553

AC:

2666

AN:

4818

European-Finnish (FIN)

AF:

0.542

AC:

5651

AN:

10428

Middle Eastern (MID)

AF:

0.630

AC:

184

AN:

292

European-Non Finnish (NFE)

AF:

0.653

AC:

44233

AN:

67700

Other (OTH)

AF:

0.578

AC:

1216

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1742

3484

5227

6969

8711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 24, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Intellectual disability, autosomal recessive 1

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

-0.010

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

PromoterAI

0.0076

Neutral

(source)

Varity_R

0.094

gMVP

0.23

Mutation Taster

=72/28

polymorphism

(source)

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

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chr4-118352557-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over