16-2785398-C-T

Variant names:

• chr16-2785398-C-T
• rs2068860999
• NM_152891.3:c.491G>A

Variant summary

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

The NM_152891.3(PRSS33):​c.491G>A​(p.Gly164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000781 in 1,281,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G164V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PRSS33 NM_152891.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 0 publications found

Genes affected

PRSS33 (HGNC:30405): (serine protease 33) Enables serine-type endopeptidase activity. Involved in protein kinase C signaling and proteolysis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS33	NM_152891.3	c.491G>A	p.Gly164Asp	missense_variant	Exon 5 of 7	ENST00000682474.1	NP_690851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS33	ENST00000682474.1	c.491G>A	p.Gly164Asp	missense_variant	Exon 5 of 7		NM_152891.3	ENSP00000507560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.81e-7 AC: 1 AN: 1281004 Hom.: 0 Cov.: 33 AF XY: 0.00000160 AC XY: 1 AN XY: 624706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26224

American (AMR) AF: 0.00 AC: 0 AN: 17930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18318

East Asian (EAS) AF: 0.00 AC: 0 AN: 32370

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036340

Other (OTH) AF: 0.00 AC: 0 AN: 53014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.
PhyloP100		2.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.9	D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.86
MutPred		0.96		Loss of methylation at R161 (P = 0.086);Loss of methylation at R161 (P = 0.086);.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.89
gMVP		0.94

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: rs2068860999; hg19: chr16-2835399;