4-70409527-C-A

Position:

chr4-70409527-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021225.5(OPRPN):c.199C>A(p.Pro67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,786 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

OPRPN
NM_021225.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.412

Variant links:

Genes affected

OPRPN (HGNC:17279): (opiorphin prepropeptide) This gene encodes a member of the proline-rich protein family. The encoded protein has multiple proposed functions, including roles in pain suppression, penile erection, and protection of the eye surface. The QRFSR pentapeptide, known as opiorphin, is derived from the N-terminal of this protein. Opiorphin inhibits the enkephalin-inactivating peptidases neprilysin and aminopeptidase N, and this activity is thought to reduce sensitivity to painful stimuli by effecting enkephalin-related activation of opioid-dependent pathways. Opiorphin may also act as an anti-depressant. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

OPRPN links:

OPRPN (HGNC:):

OPRPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18978128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPRPN	NM_021225.5 linkuse as main transcript	c.199C>A	p.Pro67Thr	missense_variant	3/3	ENST00000399575.7	NP_067048.4	Q99935
OPRPN	NM_001302807.2 linkuse as main transcript	c.255C>A	p.Ser85Ser	synonymous_variant	4/4		NP_001289736.1
OPRPN	NR_126503.2 linkuse as main transcript	n.249C>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OPRPN	ENST00000399575.7 linkuse as main transcript	c.199C>A	p.Pro67Thr	missense_variant	3/3	1	NM_021225.5	ENSP00000382485.2	Q99935
OPRPN	ENST00000505023.1 linkuse as main transcript	n.224C>A		non_coding_transcript_exon_variant	2/2	3
OPRPN	ENST00000514338.1 linkuse as main transcript	n.380C>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249576

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2021

The c.199C>A (p.P67T) alteration is located in exon 3 (coding exon 2) of the OPRPN gene. This alteration results from a C to A substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.8

DANN

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.44

M_CAP

Benign

0.017

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.045

Sift

Benign

0.066

Sift4G

Benign

0.31

Polyphen

0.89

Vest4

0.17

MutPred

0.14

Loss of glycosylation at P72 (P = 0.064);

MVP

0.33

MPC

0.39

ClinPred

0.45

GERP RS

2.0

Varity_R

0.083

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over