rs797045901

Positions:

• chr4-118308575-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003619.4(PRSS12):​c.1492T>A​(p.Phe498Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRSS12 NM_003619.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110387415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS12	NM_003619.4	c.1492T>A	p.Phe498Ile	missense_variant, splice_region_variant	8/13	ENST00000296498.3
PRSS12	XM_011532387.3	c.1492T>A	p.Phe498Ile	missense_variant, splice_region_variant	8/9
PRSS12	XM_005263318.5	c.1492T>A	p.Phe498Ile	missense_variant, splice_region_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS12	ENST00000296498.3	c.1492T>A	p.Phe498Ile	missense_variant, splice_region_variant	8/13	1	NM_003619.4	P1
PRSS12	ENST00000515089.1	n.79T>A		splice_region_variant, non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
MutationTaster	Benign	0.87	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.013
Sift	Benign	0.30	T
Sift4G	Benign	0.48	T
Polyphen		0.21	B
Vest4		0.28
MutPred		0.33		Gain of glycosylation at S495 (P = 0.0402);
MVP		0.44
MPC		0.39
ClinPred		0.25	T
GERP RS		3.3
Varity_R		0.053
gMVP		0.59

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: rs797045901; hg19: chr4-119229730;