4-118283097-G-T

Variant names:

• chr4-118283097-G-T
• rs201801258
• NM_003619.4:c.2054C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003619.4(PRSS12):​c.2054C>A​(p.Thr685Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T685I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRSS12 NM_003619.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS12	NM_003619.4	c.2054C>A	p.Thr685Asn	missense_variant	Exon 12 of 13	ENST00000296498.3	NP_003610.2
PRSS12	NM_001440549.1	c.2054C>A	p.Thr685Asn	missense_variant	Exon 12 of 13		NP_001427478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS12	ENST00000296498.3	c.2054C>A	p.Thr685Asn	missense_variant	Exon 12 of 13	1	NM_003619.4	ENSP00000296498.3
PRSS12	ENST00000510903.1	n.137C>A		non_coding_transcript_exon_variant	Exon 3 of 3	5
SNHG8	ENST00000654083.3	n.4132G>T		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.021	D
Vest4		0.45
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.19
gMVP		0.59
Mutation Taster		=66/34	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: rs201801258; hg19: chr4-119204252;