4-118352557-C-T

Variant names:

• chr4-118352557-C-T
• rs13119545
• NM_003619.4:c.164G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003619.4(PRSS12):​c.164G>A​(p.Arg55Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRSS12 NM_003619.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 25 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: Illumina, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078033656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.164G>A	p.Arg55Lys	missense_variant	Exon 1 of 13	ENST00000296498.3	NP_003610.2
PRSS12	NM_001440549.1	c.164G>A	p.Arg55Lys	missense_variant	Exon 1 of 13		NP_001427478.1
PRSS12	NM_001440550.1	c.164G>A	p.Arg55Lys	missense_variant	Exon 1 of 9		NP_001427479.1
PRSS12	NM_001440551.1	c.164G>A	p.Arg55Lys	missense_variant	Exon 1 of 10		NP_001427480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.164G>A	p.Arg55Lys	missense_variant	Exon 1 of 13	1	NM_003619.4	ENSP00000296498.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1382142 Hom.: 0 Cov.: 60 AF XY: 0.00000293 AC XY: 2 AN XY: 682290

African (AFR) AF: 0.00 AC: 0 AN: 29610

American (AMR) AF: 0.00 AC: 0 AN: 33582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24160

East Asian (EAS) AF: 0.00 AC: 0 AN: 33824

South Asian (SAS) AF: 0.00 AC: 0 AN: 77994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48946

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071456

Other (OTH) AF: 0.0000175 AC: 1 AN: 57030

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 7232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.4
DANN	Benign	0.88
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.010
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.17
Sift	Benign	0.42	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.31		Loss of glycosylation at P60 (P = 0.0022);
MVP		0.39
MPC		0.28
ClinPred		0.071	T
GERP RS		1.3
PromoterAI		-0.0021	Neutral
Varity_R		0.13
gMVP		0.22
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs13119545; hg19: chr4-119273712;