16-58284600-G-A

Position:

• chr16-58284600-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001305173.2(PRSS54):​c.644C>T​(p.Thr215Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRSS54 NM_001305173.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.629

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]

PRSS54 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26556668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS54	NM_001305173.2	c.644C>T	p.Thr215Ile	missense_variant	6/7	ENST00000567164.6	NP_001292102.1
PRSS54	NM_001080492.2	c.644C>T	p.Thr215Ile	missense_variant	6/7		NP_001073961.1
PRSS54	NM_001305174.2	c.347C>T	p.Thr116Ile	missense_variant	5/6		NP_001292103.1
PRSS54	XM_047433779.1	c.110C>T	p.Thr37Ile	missense_variant	2/3		XP_047289735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS54	ENST00000567164.6	c.644C>T	p.Thr215Ile	missense_variant	6/7	1	NM_001305173.2	ENSP00000455024.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461714 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.644C>T (p.T215I) alteration is located in exon 6 (coding exon 4) of the PRSS54 gene. This alteration results from a C to T substitution at nucleotide position 644, causing the threonine (T) at amino acid position 215 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.64	.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.095	T;T;T;T
Sift4G	Benign	0.36	T;T;T;.
Polyphen		0.75	P;P;.;.
Vest4		0.29
MutPred		0.67		Loss of disorder (P = 0.0187);Loss of disorder (P = 0.0187);.;.;
MVP		0.50
MPC		0.24
ClinPred		0.29	T
GERP RS		-0.39
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1567514299; hg19: chr16-58318504;