9-33798555-A-G

Variant names:

• chr9-33798555-A-G
• rs1048379
• NM_002771.4:c.524A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002771.4(PRSS3):​c.524A>G​(p.Tyr175Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRSS3 NM_002771.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.18
• Publications: 2 publications found

Genes affected

PRSS3 (HGNC:9486): (serine protease 3) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is expressed in the brain and pancreas and is resistant to common trypsin inhibitors. It is active on peptide linkages involving the carboxyl group of lysine or arginine. This gene is localized to the locus of T cell receptor beta variable orphans on chromosome 9. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2010]

UBE2R2-AS1 (HGNC:49911): (UBE2R2 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002771.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS3	NM_002771.4	MANE Select	c.524A>G	p.Tyr175Cys	missense	Exon 4 of 5	NP_002762.3
	PRSS3	NM_001197097.3		c.566A>G	p.Tyr189Cys	missense	Exon 5 of 6	NP_001184026.3
	PRSS3	NM_001197098.1		c.503A>G	p.Tyr168Cys	missense	Exon 4 of 5	NP_001184027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS3	ENST00000379405.4	TSL:1 MANE Select	c.524A>G	p.Tyr175Cys	missense	Exon 4 of 5	ENSP00000368715.3
	PRSS3	ENST00000342836.9	TSL:1	c.560A>G	p.Tyr187Cys	missense	Exon 5 of 6	ENSP00000340889.5
	PRSS3	ENST00000429677.8	TSL:1	c.503A>G	p.Tyr168Cys	missense	Exon 4 of 5	ENSP00000401828.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.67
Sift	Benign	0.031	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.81		Gain of ubiquitination at K229 (P = 0.078)
MVP		0.95
MPC		0.98
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.90
gMVP		0.80
Mutation Taster		=29/71	disease causing

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: rs1048379; hg19: chr9-33798553;