chr4-118280341-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
• Publications: 1 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 -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 VariationId 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 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	NM_003619.4	MANE Select	c.*1595A>G		3_prime_UTR	Exon 13 of 13	NP_003610.2	P56730
	PRSS12	NM_001440549.1		c.*1693A>G		3_prime_UTR	Exon 13 of 13	NP_001427478.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS12	ENST00000296498.3	TSL:1 MANE Select	c.*1595A>G		3_prime_UTR	Exon 13 of 13	ENSP00000296498.3	P56730
	SNHG8	ENST00000654083.3		n.1376T>C		non_coding_transcript_exon	Exon 3 of 3
	PRSS12	ENST00000864359.1		c.*1595A>G		downstream_gene	N/A	ENSP00000534418.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal recessive 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs145858385; hg19: chr4-119201496;