rs77322543

chr4-118316204-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003619.4(PRSS12):c.1270G>A(p.Val424Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,613,994 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V424V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: PRSS12 NM_003619.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01632011).
• BP6: Variant 4-118316204-C-T is Benign according to our data. Variant chr4-118316204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (797/152158) while in subpopulation AFR AF= 0.0182 (754/41500). AF 95% confidence interval is 0.0171. There are 14 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS12	NM_003619.4	c.1270G>A	p.Val424Ile	missense_variant	6/13	ENST00000296498.3
PRSS12	XM_011532387.3	c.1270G>A	p.Val424Ile	missense_variant	6/9
PRSS12	XM_005263318.5	c.1270G>A	p.Val424Ile	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS12	ENST00000296498.3	c.1270G>A	p.Val424Ile	missense_variant	6/13	1	NM_003619.4	P1
PRSS12	ENST00000503043.1	n.298G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 796 AN: 152040 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00133 AC: 335 AN: 251284 Hom.: 4 AF XY: 0.000957 AC XY: 130 AN XY: 135784

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461836 Hom.: 2 Cov.: 34 AF XY: 0.000421 AC XY: 306 AN XY: 727232

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00524 AC: 797 AN: 152158 Hom.: 14 Cov.: 31 AF XY: 0.00489 AC XY: 364 AN XY: 74372

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000832 Hom.: 3

Bravo AF: 0.00585

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.094	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.22
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.96	D
Vest4		0.30
MVP		0.61
MPC		0.58
ClinPred		0.058	T
GERP RS		6.2
Varity_R		0.11
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs77322543; hg19: chr4-119237359;