4-118280432-C-T

Variant names:

• chr4-118280432-C-T
• rs1045817
• NM_003619.4:c.*1504G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003619.4(PRSS12):​c.*1504G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,246 control chromosomes in the GnomAD database, including 1,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1328 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: PRSS12 NM_003619.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05

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 4-118280432-C-T is Benign according to our data. Variant chr4-118280432-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 347374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.*1504G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000296498.3	NP_003610.2
PRSS12	NM_001440549.1	c.*1602G>A		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.*1504G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_003619.4	ENSP00000296498.3
SNHG8	ENST00000654083.3	n.1467C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17251 AN: 152126 Hom.: 1331 Cov.: 33

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.0571

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.106

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

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) AC: 0 AN: 0

GnomAD4 genome AF: 0.113 AC: 17251 AN: 152246 Hom.: 1328 Cov.: 33 AF XY: 0.118 AC XY: 8793 AN XY: 74418

African (AFR) AF: 0.0262 AC: 1088 AN: 41560

American (AMR) AF: 0.112 AC: 1708 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 318 AN: 3468

East Asian (EAS) AF: 0.0562 AC: 291 AN: 5176

South Asian (SAS) AF: 0.196 AC: 946 AN: 4826

European-Finnish (FIN) AF: 0.224 AC: 2376 AN: 10586

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10202 AN: 68006

Other (OTH) AF: 0.107 AC: 227 AN: 2114

Alfa AF: 0.129 Hom.: 417

Bravo AF: 0.0965

Asia WGS AF: 0.131 AC: 455 AN: 3478

ClinVar

Significance: Likely 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: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	0.82
DANN	Benign	0.63
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1045817; hg19: chr4-119201587;