4-72128775-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004885.3(NPFFR2):c.184G>A(p.Gly62Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPFFR2 NM_004885.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPFFR2	NM_004885.3	c.184G>A	p.Gly62Arg	missense_variant	2/4	ENST00000308744.12
NPFFR2	NM_001144756.2	c.193G>A	p.Gly65Arg	missense_variant	3/5
NPFFR2	NM_053036.3	c.184G>A	p.Gly62Arg	missense_variant	2/4
NPFFR2	XM_011531554.3	c.305-9265G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPFFR2	ENST00000308744.12	c.184G>A	p.Gly62Arg	missense_variant	2/4	1	NM_004885.3	P4
NPFFR2	ENST00000395999.5	c.193G>A	p.Gly65Arg	missense_variant	3/5	1		A2
NPFFR2	ENST00000358749.3	c.184G>A	p.Gly62Arg	missense_variant	2/4	1		P4
NPFFR2	ENST00000344413.6	c.-20-9265G>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251374 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.490G>A (p.G164R) 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 490, causing the glycine (G) at amino acid position 164 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	5.0	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.73		Loss of sheet (P = 0.0817);.;.;
MVP		0.87
MPC		0.24
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.92

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: rs1468143710; hg19: chr4-72994492;