rs373311928

Variant names:

• chr4-118352412-C-G
• rs373311928
• NM_003619.4:c.309G>C
• PRSS12 p.Thr103Thr

Your query was ambiguous. Multiple possible variants found:

• chr4-118352412-C-G
• chr4-118352412-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_003619.4(PRSS12):​c.309G>C​(p.Thr103Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,534,716 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: PRSS12 NM_003619.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 4-118352412-C-G is Benign according to our data. Variant chr4-118352412-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 211962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 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.309G>C	p.Thr103Thr	synonymous	Exon 1 of 13	NP_003610.2	P56730
	PRSS12	NM_001440549.1		c.309G>C	p.Thr103Thr	synonymous	Exon 1 of 13	NP_001427478.1
	PRSS12	NM_001440550.1		c.309G>C	p.Thr103Thr	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.309G>C	p.Thr103Thr	synonymous	Exon 1 of 13	ENSP00000296498.3	P56730
	PRSS12	ENST00000864359.1		c.309G>C	p.Thr103Thr	synonymous	Exon 1 of 11	ENSP00000534418.1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000517 AC: 67 AN: 129688 AF XY: 0.000478

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.000388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000261

GnomAD4 exome AF: 0.000242 AC: 335 AN: 1382578 Hom.: 1 Cov.: 30 AF XY: 0.000202 AC XY: 138 AN XY: 681854

African (AFR) AF: 0.00907 AC: 284 AN: 31322

American (AMR) AF: 0.000484 AC: 17 AN: 35100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24814

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 78214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37458

Middle Eastern (MID) AF: 0.000371 AC: 2 AN: 5390

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076922

Other (OTH) AF: 0.000538 AC: 31 AN: 57616

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74372

African (AFR) AF: 0.00893 AC: 371 AN: 41544

American (AMR) AF: 0.000589 AC: 9 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000907 Hom.: 0

Bravo AF: 0.00294

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.75
PhyloP100		-1.4
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373311928;

hg19: chr4-119273567;