rs144853134

Positions:

• chr4-118352670-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003619.4(PRSS12):​c.51A>G​(p.Glu17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,613,282 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (49 hom.)
• Consequence: PRSS12 NM_003619.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.839

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-118352670-T-C is Benign according to our data. Variant chr4-118352670-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.839 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.51A>G	p.Glu17=	synonymous_variant	1/13	ENST00000296498.3	NP_003610.2
PRSS12	XM_011532387.3	c.51A>G	p.Glu17=	synonymous_variant	1/9		XP_011530689.1
PRSS12	XM_005263318.5	c.51A>G	p.Glu17=	synonymous_variant	1/10		XP_005263375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.51A>G	p.Glu17=	synonymous_variant	1/13	1	NM_003619.4	ENSP00000296498	P1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152074 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00436 AC: 1084 AN: 248396 Hom.: 5 AF XY: 0.00449 AC XY: 605 AN XY: 134790

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00538

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00678

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00711 AC: 10393 AN: 1461100 Hom.: 49 Cov.: 42 AF XY: 0.00699 AC XY: 5083 AN XY: 726856

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.00257

Gnomad4 NFE exome AF: 0.00834

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152182 Hom.: 4 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74402

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00619 Hom.: 5

Bravo AF: 0.00430

Asia WGS AF: 0.00116 AC: 4 AN: 3468

EpiCase AF: 0.00632

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PRSS12: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 16, 2015

- -

Intellectual disability, autosomal recessive 1 Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.7
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144853134; hg19: chr4-119273825;