NM_003619.4:c.51A>G

Variant names:

• chr4-118352670-T-C
• rs144853134
• NM_003619.4:c.51A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003619.4(PRSS12):​c.51A>G​(p.Glu17Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,613,282 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (49 hom.)
• Consequence: PRSS12 NM_003619.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.839
• Publications: 1 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-118352670-T-C is Benign according to our data. Variant chr4-118352670-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.839 with no splicing effect.
• 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.51A>G	p.Glu17Glu	synonymous	Exon 1 of 13	NP_003610.2
	PRSS12	NM_001440549.1		c.51A>G	p.Glu17Glu	synonymous	Exon 1 of 13	NP_001427478.1
	PRSS12	NM_001440550.1		c.51A>G	p.Glu17Glu	synonymous	Exon 1 of 9	NP_001427479.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	ENST00000296498.3	TSL:1 MANE Select	c.51A>G	p.Glu17Glu	synonymous	Exon 1 of 13	ENSP00000296498.3
	PRSS12	ENST00000864359.1		c.51A>G	p.Glu17Glu	synonymous	Exon 1 of 11	ENSP00000534418.1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152074 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00436 AC: 1084 AN: 248396 AF XY: 0.00449

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00678

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00711 AC: 10393 AN: 1461100 Hom.: 49 Cov.: 42 AF XY: 0.00699 AC XY: 5083 AN XY: 726856

African (AFR) AF: 0.00123 AC: 41 AN: 33448

American (AMR) AF: 0.00177 AC: 79 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00548 AC: 472 AN: 86138

European-Finnish (FIN) AF: 0.00257 AC: 137 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00834 AC: 9272 AN: 1111588

Other (OTH) AF: 0.00641 AC: 387 AN: 60348

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152182 Hom.: 4 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74402

African (AFR) AF: 0.00193 AC: 80 AN: 41540

American (AMR) AF: 0.00222 AC: 34 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00762 AC: 518 AN: 67980

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00600 Hom.: 5

Bravo AF: 0.00430

Asia WGS AF: 0.00116 AC: 4 AN: 3468

EpiCase AF: 0.00632

EpiControl AF: 0.00705

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Intellectual disability, autosomal recessive 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		0.84
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144853134; hg19: chr4-119273825;