12-53506856-A-G

Position:

• chr12-53506856-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003717.4(NPFF):​c.262T>C​(p.Trp88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,604,760 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (86 hom.)
• Consequence: NPFF NM_003717.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.829

Genes affected

NPFF (HGNC:7901): (neuropeptide FF-amide peptide precursor) This gene encodes a member of the FMRFamide related peptide (FARP) family of neuropeptides. The encoded preproprotein is proteolytically processed to generate multiple amidated peptides. These peptides may play a role in the regulation of heart rate and blood pressure and the modulation of morphine-induced antinociception. Patients with hypertension exhibit decreased expression of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ATF7-NPFF (HGNC:55073): (ATF7-NPFF readthrough) Predicted to enable DNA binding activity and DNA-binding transcription factor activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NPFF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015759766).
• BP6: Variant 12-53506856-A-G is Benign according to our data. Variant chr12-53506856-A-G is described in ClinVar as [Benign]. Clinvar id is 776710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPFF	NM_003717.4	c.262T>C	p.Trp88Arg	missense_variant	3/3	ENST00000267017.4	NP_003708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPFF	ENST00000267017.4	c.262T>C	p.Trp88Arg	missense_variant	3/3	1	NM_003717.4	ENSP00000267017.3
ATF7-NPFF	ENST00000591834	c.*2T>C		3_prime_UTR_variant	13/13	5		ENSP00000466174.1
NPFF	ENST00000448979.4	n.502T>C		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2901 AN: 152140 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00728 AC: 1769 AN: 242936 Hom.: 37 AF XY: 0.00584 AC XY: 765 AN XY: 131086

Gnomad AFR exome AF: 0.0637

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00291 AC: 4229 AN: 1452502 Hom.: 86 Cov.: 31 AF XY: 0.00266 AC XY: 1918 AN XY: 721782

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.0000788

Gnomad4 EAS exome AF: 0.0293

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000494

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.0191 AC: 2904 AN: 152258 Hom.: 71 Cov.: 32 AF XY: 0.0177 AC XY: 1321 AN XY: 74436

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0279

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00455 Hom.: 20

Bravo AF: 0.0209

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0631 AC: 278

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00830 AC: 1007

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.77
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.097	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	4.8	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.10		Loss of catalytic residue at P91 (P = 0.0269);
MVP		0.072
MPC		0.40
ClinPred		0.0013	T
GERP RS		-2.8
Varity_R		0.049
gMVP		0.018

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs35822762; hg19: chr12-53900640; COSMIC: COSV57200644; COSMIC: COSV57200644;