NM_003619.4:c.936C>T

Variant names:

• chr4-118331751-G-A
• rs12505679
• NM_003619.4:c.936C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_003619.4(PRSS12):​c.936C>T​(p.Ala312Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A312A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: PRSS12 NM_003619.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.92
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-118331751-G-A is Benign according to our data. Variant chr4-118331751-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436431.
• BP7: Synonymous conserved (PhyloP=-4.92 with no splicing effect.

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.936C>T	p.Ala312Ala	synonymous	Exon 4 of 13	NP_003610.2	P56730
	PRSS12	NM_001440549.1		c.936C>T	p.Ala312Ala	synonymous	Exon 4 of 13	NP_001427478.1
	PRSS12	NM_001440550.1		c.936C>T	p.Ala312Ala	synonymous	Exon 4 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.936C>T	p.Ala312Ala	synonymous	Exon 4 of 13	ENSP00000296498.3	P56730
	PRSS12	ENST00000864359.1		c.618C>T	p.Ala206Ala	synonymous	Exon 2 of 11	ENSP00000534418.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250854 AF XY: 0.0000738

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727236

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1112004

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74404

African (AFR) AF: 0.000193 AC: 8 AN: 41542

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.063
DANN	Benign	0.40
PhyloP100		-4.9

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: rs12505679; hg19: chr4-119252906; COSMIC: COSV56605703;