16-58284652-A-T

Variant names:

• chr16-58284652-A-T
• rs147993353
• NM_001305173.2:c.592T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001305173.2(PRSS54):​c.592T>A​(p.Tyr198Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. Y198H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRSS54 NM_001305173.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• Publications: 0 publications found

Genes affected

PRSS54 (HGNC:26336): (serine protease 54) This gene encodes a putative serine-type endopeptidase containing the peptidase S1 domain. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085413456).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305173.2. 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
	PRSS54	NM_001305173.2	MANE Select	c.592T>A	p.Tyr198Asn	missense	Exon 6 of 7	NP_001292102.1	Q6PEW0
	PRSS54	NM_001080492.2		c.592T>A	p.Tyr198Asn	missense	Exon 6 of 7	NP_001073961.1	Q6PEW0
	PRSS54	NM_001305174.2		c.295T>A	p.Tyr99Asn	missense	Exon 5 of 6	NP_001292103.1	F5H6C6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS54	ENST00000567164.6	TSL:1 MANE Select	c.592T>A	p.Tyr198Asn	missense	Exon 6 of 7	ENSP00000455024.1	Q6PEW0
	PRSS54	ENST00000219301.8	TSL:5	c.592T>A	p.Tyr198Asn	missense	Exon 6 of 7	ENSP00000219301.4	Q6PEW0
	PRSS54	ENST00000543437.5	TSL:2	c.295T>A	p.Tyr99Asn	missense	Exon 5 of 6	ENSP00000437705.1	F5H6C6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

⚠️ 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: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	1.2
DANN	Benign	0.66
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.56	N
PhyloP100		-0.43
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.60	N
REVEL	Uncertain	0.30
Sift	Benign	0.32	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.58		Gain of disorder (P = 0.0132)
MVP		0.36
MPC		0.23
ClinPred		0.046	T
GERP RS		-4.2
Varity_R		0.086
gMVP		0.51

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: rs147993353; hg19: chr16-58318556;