rs876657372

Positions:

• chr4-118313331-GACGT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000296498.3(PRSS12):​c.1355_1358del​(p.Asp452AlafsTer50) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classifications from unflagged records (no stars). Synonymous variant affecting the same amino acid position (i.e. D452D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRSS12 ENST00000296498.3 frameshift
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 8.24

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-118313331-GACGT-G is Pathogenic according to our data. Variant chr4-118313331-GACGT-G is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 4101.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.1355_1358del	p.Asp452AlafsTer50	frameshift_variant	7/13	ENST00000296498.3	NP_003610.2
PRSS12	XM_005263318.5	c.1355_1358del	p.Asp452AlafsTer50	frameshift_variant	7/10		XP_005263375.1
PRSS12	XM_011532387.3	c.1355_1358del	p.Asp452AlafsTer50	frameshift_variant	7/9		XP_011530689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.1355_1358del	p.Asp452AlafsTer50	frameshift_variant	7/13	1	NM_003619.4	ENSP00000296498	P1
PRSS12	ENST00000503043.1	n.383_386del		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Intellectual disability, autosomal recessive 1 Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Nov 29, 2002

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs876657372; hg19: chr4-119234486;