rs183541303

Variant names:

• chr4-118308584-C-T
• rs183541303
• NM_003619.4:c.1490-7G>A

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0004879
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.427
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 211957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003619.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	NM_003619.4	MANE Select	c.1490-7G>A		splice_region intron	N/A	NP_003610.2	P56730
	PRSS12	NM_001440549.1		c.1490-7G>A		splice_region intron	N/A	NP_001427478.1
	PRSS12	NM_001440550.1		c.1490-7G>A		splice_region intron	N/A	NP_001427479.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	ENST00000296498.3	TSL:1 MANE Select	c.1490-7G>A		splice_region intron	N/A	ENSP00000296498.3	P56730
	PRSS12	ENST00000864359.1		c.1172-7G>A		splice_region intron	N/A	ENSP00000534418.1
	PRSS12	ENST00000515089.1	TSL:2	n.77-7G>A		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.000609 AC: 153 AN: 251118 AF XY: 0.000361

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 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

African (AFR) AF: 0.0103 AC: 329 AN: 31892

American (AMR) AF: 0.000231 AC: 10 AN: 43198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24144

East Asian (EAS) AF: 0.00 AC: 0 AN: 36530

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48644

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5470

European-Non Finnish (NFE) AF: 0.0000591 AC: 64 AN: 1083578

Other (OTH) AF: 0.000455 AC: 26 AN: 57122

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

African (AFR) AF: 0.00806 AC: 334 AN: 41416

American (AMR) AF: 0.000854 AC: 13 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67876

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00275

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.56
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs183541303; hg19: chr4-119229739;