rs745313899

Positions:

• chr7-141836460-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001008270.3(PRSS37):​c.643G>A​(p.Val215Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PRSS37 NM_001008270.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.60

Genes affected

PRSS37 (HGNC:29211): (serine protease 37) Predicted to enable serine-type endopeptidase activity. Involved in positive regulation of acrosome reaction and regulation of protein processing. Located in acrosomal vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21295437).
• BP6: Variant 7-141836460-C-T is Benign according to our data. Variant chr7-141836460-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436439.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS37	NM_001008270.3	c.643G>A	p.Val215Ile	missense_variant	5/5	ENST00000350549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS37	ENST00000350549.8	c.643G>A	p.Val215Ile	missense_variant	5/5	1	NM_001008270.3	P1
PRSS37	ENST00000452758.1	c.*413G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
PRSS37	ENST00000438520.1	c.643G>A	p.Val215Ile	missense_variant	6/6	5		P1
PRSS37	ENST00000419085.5	c.*1417G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251480 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461320 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2022	The c.643G>A (p.V215I) alteration is located in exon 5 (coding exon 5) of the PRSS37 gene. This alteration results from a G to A substitution at nucleotide position 643, causing the valine (V) 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.046	D;D
Sift4G	Benign	0.33	T;T
Polyphen		0.43	B;B
Vest4		0.13
MVP		0.73
MPC		0.16
ClinPred		0.079	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.082

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

Publications

LitVar

Other links and lift over

dbSNP: rs745313899; hg19: chr7-141536260; COSMIC: COSV63339390;