chr4-118282175-G-A

Position:

• chr4-118282175-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 130046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.2389C>T	p.Arg797Cys	missense_variant	13/13	ENST00000296498.3	NP_003610.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.2389C>T	p.Arg797Cys	missense_variant	13/13	1	NM_003619.4	ENSP00000296498.3
SNHG8	ENST00000654083.2	n.3025G>A		non_coding_transcript_exon_variant	3/3

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

GnomAD3 exomes AF: 0.00362 AC: 911 AN: 251492 Hom.: 5 AF XY: 0.00382 AC XY: 519 AN XY: 135920

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 SAS exome AF: 0.00265

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

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.00752

Gnomad4 OTH exome AF: 0.00485

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

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00565 Hom.: 6

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PRSS12: BS2; SNHG8: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 17, 2017

- -

Intellectual disability, autosomal recessive 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs35996030; hg19: chr4-119203330;