4-118280341-T-C

Variant names:

• chr4-118280341-T-C
• rs145858385
• NM_003619.4:c.*1595A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003619.4(PRSS12):​c.*1595A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00932 in 152,128 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS12 NM_003619.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.538

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-118280341-T-C is Benign according to our data. Variant chr4-118280341-T-C is described in ClinVar as [Benign]. Clinvar id is 902340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00932 (1418/152128) while in subpopulation SAS AF = 0.0248 (119/4802). AF 95% confidence interval is 0.0212. There are 26 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.*1595A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000296498.3	NP_003610.2
PRSS12	NM_001440549.1	c.*1693A>G		3_prime_UTR_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.*1595A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_003619.4	ENSP00000296498.3
SNHG8	ENST00000654083.3	n.1376T>C		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00934 AC: 1420 AN: 152010 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0839

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.0188

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00932 AC: 1418 AN: 152128 Hom.: 26 Cov.: 33 AF XY: 0.00889 AC XY: 661 AN XY: 74370

African (AFR) AF: 0.00214 AC: 89 AN: 41574

American (AMR) AF: 0.0112 AC: 171 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 291 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0248 AC: 119 AN: 4802

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10592

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 67974

Other (OTH) AF: 0.0186 AC: 39 AN: 2100

Alfa AF: 0.0105 Hom.: 7

Bravo AF: 0.00952

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.46
PhyloP100		-0.54
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

Publications

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Other links and lift over

dbSNP: rs145858385; hg19: chr4-119201496;