Variant chr4-72128592-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_004885.3(NPFFR2):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000163 in 1,593,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NPFFR2
NM_004885.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

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 Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPFFR2	NM_004885.3 link	c.1A>G	p.Met1?	start_lost	2/4	ENST00000308744.12	NP_004876.3	Q9Y5X5-2A0PJM9
NPFFR2	NM_053036.3 link	c.1A>G	p.Met1?	start_lost	2/4		NP_444264.1	Q9Y5X5-2A0PJM9
NPFFR2	NM_001144756.2 link	c.10A>G	p.Met4Val	missense_variant	3/5		NP_001138228.1	Q9Y5X5-3A0PJM9
NPFFR2	XM_011531554.3 link	c.305-9448A>G		intron_variant			XP_011529856.2	A0A804CC06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPFFR2	ENST00000308744.12 link	c.1A>G	p.Met1?	start_lost	2/4	1	NM_004885.3	ENSP00000307822.7	Q9Y5X5-2
NPFFR2	ENST00000358749.3 link	c.1A>G	p.Met1?	start_lost	2/4	1		ENSP00000351599.3	Q9Y5X5-2
NPFFR2	ENST00000395999.5 link	c.10A>G	p.Met4Val	missense_variant	3/5	1		ENSP00000379321.1	Q9Y5X5-3
NPFFR2	ENST00000344413.6 link	c.-20-9448A>G		intron_variant		1		ENSP00000340789.6	A0A804CC06

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000288

AC:

AN:

242808

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

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:

0.000170

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1441598

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

715514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000256

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:

0.00000819

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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 07, 2024

The c.307A>G (p.M103V) alteration is located in exon 2 (coding exon 2) of the NPFFR2 gene. This alteration results from a A to G substitution at nucleotide position 307, causing the methionine (M) at amino acid position 103 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0042

T;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.51

T;T;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.0

N;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.85

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.16

T;D;D

Sift4G

Benign

0.082

T;.;D

Polyphen

1.0

D;D;.

Vest4

0.66

MutPred

0.56

Loss of disorder (P = 0.1133);.;.;

MVP

0.91

MPC

0.12

ClinPred

0.48

GERP RS

5.9

Varity_R

0.25

gMVP

0.50

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