Variant 4-72128806-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004885.3(NPFFR2):c.215G>A(p.Arg72Lys) 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 1,461,742 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: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPFFR2
NM_004885.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

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:

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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=0.20945483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NPFFR2	NM_004885.3 linkuse as main transcript	c.215G>A	p.Arg72Lys	missense_variant	2/4	ENST00000308744.12	NP_004876.3
NPFFR2	NM_001144756.2 linkuse as main transcript	c.224G>A	p.Arg75Lys	missense_variant	3/5		NP_001138228.1
NPFFR2	NM_053036.3 linkuse as main transcript	c.215G>A	p.Arg72Lys	missense_variant	2/4		NP_444264.1
NPFFR2	XM_011531554.3 linkuse as main transcript	c.305-9234G>A		intron_variant			XP_011529856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPFFR2	ENST00000308744.12 linkuse as main transcript	c.215G>A	p.Arg72Lys	missense_variant	2/4	1	NM_004885.3	ENSP00000307822	P4	Q9Y5X5-2
NPFFR2	ENST00000395999.5 linkuse as main transcript	c.224G>A	p.Arg75Lys	missense_variant	3/5	1		ENSP00000379321	A2	Q9Y5X5-3
NPFFR2	ENST00000358749.3 linkuse as main transcript	c.215G>A	p.Arg72Lys	missense_variant	2/4	1		ENSP00000351599	P4	Q9Y5X5-2
NPFFR2	ENST00000344413.6 linkuse as main transcript	c.-20-9234G>A		intron_variant		1		ENSP00000340789

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 29, 2024

The c.521G>A (p.R174K) alteration is located in exon 2 (coding exon 2) of the NPFFR2 gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a lysine (K). 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

0.077

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.0075

T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.59

T;T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.84

L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.30

N;N;N

REVEL

Benign

0.035

Sift

Benign

0.61

T;T;T

Sift4G

Benign

0.64

T;.;T

Polyphen

0.033

B;B;.

Vest4

0.28

MutPred

0.73

Gain of ubiquitination at R174 (P = 0.0351);.;.;

MVP

0.33

MPC

0.041

ClinPred

0.088

GERP RS

1.3

Varity_R

0.039

gMVP

0.53

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over