4-118308584-C-T

Position:

• chr4-118308584-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003619.4(PRSS12):​c.1490-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 1,567,858 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: PRSS12 NM_003619.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004879
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.427

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 4-118308584-C-T is Benign according to our data. Variant chr4-118308584-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-118308584-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS12	NM_003619.4	c.1490-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000296498.3
PRSS12	XM_005263318.5	c.1490-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PRSS12	XM_011532387.3	c.1490-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS12	ENST00000296498.3	c.1490-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003619.4	P1
PRSS12	ENST00000515089.1	n.77-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 352 AN: 151500 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00809

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000855

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000609 AC: 153 AN: 251118 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135722

Gnomad AFR exome AF: 0.00874

Gnomad AMR exome AF: 0.000260

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000304 AC: 431 AN: 1416242 Hom.: 2 Cov.: 33 AF XY: 0.000224 AC XY: 158 AN XY: 704900

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000591

Gnomad4 OTH exome AF: 0.000455

GnomAD4 genome AF: 0.00232 AC: 352 AN: 151616 Hom.: 4 Cov.: 32 AF XY: 0.00209 AC XY: 155 AN XY: 74140

Gnomad4 AFR AF: 0.00806

Gnomad4 AMR AF: 0.000854

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00275

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PRSS12: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs183541303; hg19: chr4-119229739;