4-118282175-G-A

Variant names:

• chr4-118282175-G-A
• rs35996030
• NM_003619.4:c.2389C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003619.4(PRSS12):​c.2389C>T​(p.Arg797Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00595 in 1,614,120 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R797H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (46 hom.)
• Consequence: PRSS12 NM_003619.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.17
• Publications: 13 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]

SNHG8 (HGNC:33098): (small nucleolar RNA host gene 8)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01575455).
• BP6: Variant 4-118282175-G-A is Benign according to our data. Variant chr4-118282175-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 130046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 46 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	NM_003619.4	MANE Select	c.2389C>T	p.Arg797Cys	missense	Exon 13 of 13	NP_003610.2
	PRSS12	NM_001440549.1		c.2334C>T	p.Asn778Asn	synonymous	Exon 13 of 13	NP_001427478.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	ENST00000296498.3	TSL:1 MANE Select	c.2389C>T	p.Arg797Cys	missense	Exon 13 of 13	ENSP00000296498.3
	SNHG8	ENST00000654083.3		n.3210G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00362 AC: 911 AN: 251492 AF XY: 0.00382

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00618

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00620 AC: 9068 AN: 1461890 Hom.: 46 Cov.: 31 AF XY: 0.00619 AC XY: 4500 AN XY: 727248

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86258

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00752 AC: 8357 AN: 1112008

Other (OTH) AF: 0.00485 AC: 293 AN: 60396

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74430

African (AFR) AF: 0.00147 AC: 61 AN: 41540

American (AMR) AF: 0.00131 AC: 20 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00542 Hom.: 7

Bravo AF: 0.00334

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00379 AC: 460

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00462

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRSS12: BS2; SNHG8: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Apr 17, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, autosomal recessive 1 Benign:1

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.91
MPC		1.1
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.73
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35996030; hg19: chr4-119203330;