4-72146992-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004885.3(NPFFR2):c.443T>C(p.Val148Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,162 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (20 hom.)
• Consequence: NPFFR2 NM_004885.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.89

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009416938).
• BP6: Variant 4-72146992-T-C is Benign according to our data. Variant chr4-72146992-T-C is described in ClinVar as [Benign]. Clinvar id is 775989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00829 (1262/152268) while in subpopulation AFR AF= 0.029 (1205/41526). AF 95% confidence interval is 0.0277. There are 28 homozygotes in gnomad4. There are 611 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPFFR2	NM_004885.3	c.443T>C	p.Val148Ala	missense_variant	4/4	ENST00000308744.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPFFR2	ENST00000308744.12	c.443T>C	p.Val148Ala	missense_variant	4/4	1	NM_004885.3	P4

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152150 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00219 AC: 547 AN: 250084 Hom.: 7 AF XY: 0.00174 AC XY: 235 AN XY: 135136

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00392

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000974 AC: 1422 AN: 1459894 Hom.: 20 Cov.: 31 AF XY: 0.000858 AC XY: 623 AN XY: 726140

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00281

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00829 AC: 1262 AN: 152268 Hom.: 28 Cov.: 32 AF XY: 0.00820 AC XY: 611 AN XY: 74470

Gnomad4 AFR AF: 0.0290

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00199 Hom.: 9

Bravo AF: 0.00895

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00270 AC: 328

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		0.97	D;P;.
Vest4		0.70
MVP		0.58
MPC		0.21
ClinPred		0.036	T
GERP RS		5.8
Varity_R		0.36
gMVP		0.85

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: rs61733659; hg19: chr4-73012709;