4-72128604-T-C

Variant summary

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

The NM_004885.3(NPFFR2):c.13T>C(p.Trp5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,602,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NPFFR2
NM_004885.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.136

Variant links:

Genes affected

NPFFR2 (HGNC:4525): (neuropeptide FF receptor 2) This gene encodes a member of a subfamily of G-protein-coupled neuropeptide receptors. This protein is activated by the neuropeptides A-18-amide (NPAF) and F-8-amide (NPFF) and may function in pain modulation and regulation of the opioid system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

NPFFR2 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=0.06812146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPFFR2	NM_004885.3 linkuse as main transcript	c.13T>C	p.Trp5Arg	missense_variant	2/4	ENST00000308744.12
NPFFR2	NM_001144756.2 linkuse as main transcript	c.22T>C	p.Trp8Arg	missense_variant	3/5
NPFFR2	NM_053036.3 linkuse as main transcript	c.13T>C	p.Trp5Arg	missense_variant	2/4
NPFFR2	XM_011531554.3 linkuse as main transcript	c.305-9436T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPFFR2	ENST00000308744.12 linkuse as main transcript	c.13T>C	p.Trp5Arg	missense_variant	2/4	1	NM_004885.3	P4	Q9Y5X5-2
NPFFR2	ENST00000395999.5 linkuse as main transcript	c.22T>C	p.Trp8Arg	missense_variant	3/5	1		A2	Q9Y5X5-3
NPFFR2	ENST00000358749.3 linkuse as main transcript	c.13T>C	p.Trp5Arg	missense_variant	2/4	1		P4	Q9Y5X5-2
NPFFR2	ENST00000344413.6 linkuse as main transcript	c.-20-9436T>C		intron_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

246962

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1450150

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

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:

0.0000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

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

Oct 27, 2022

The c.319T>C (p.W107R) alteration is located in exon 2 (coding exon 2) of the NPFFR2 gene. This alteration results from a T to C substitution at nucleotide position 319, causing the tryptophan (W) at amino acid position 107 to be replaced by an arginine (R). 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

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.057

T;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.37

T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.068

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.52

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.044

D;T;T

Sift4G

Uncertain

0.012

D;.;D

Polyphen

0.013

B;B;.

Vest4

0.30

MutPred

0.52

Gain of disorder (P = 0.0092);.;.;

MVP

0.57

MPC

0.039

ClinPred

0.071

GERP RS

3.5

Varity_R

0.073

gMVP

0.36

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

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