rs8192593

Positions:

• chr12-53507321-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001320296.2(NPFF):​c.-68C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 1,611,386 control chromosomes in the GnomAD database, including 939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.022 (51 hom., cov: 32)
  • Exomes 𝑓: 0.033 (888 hom.)
• Consequence: NPFF NM_001320296.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (3386/152256) while in subpopulation NFE AF= 0.0361 (2455/68000). AF 95% confidence interval is 0.0349. There are 51 homozygotes in gnomad4. There are 1575 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPFF	NM_003717.4	c.102+52C>T		intron_variant		ENST00000267017.4	NP_003708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPFF	ENST00000267017.4	c.102+52C>T		intron_variant		1	NM_003717.4	ENSP00000267017.3
ATF7-NPFF	ENST00000591834.1	c.1235-179C>T		intron_variant		5		ENSP00000466174.1
NPFF	ENST00000448979.4	n.164C>T		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3386 AN: 152138 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00722

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0173

GnomAD4 exome AF: 0.0328 AC: 47830 AN: 1459130 Hom.: 888 Cov.: 32 AF XY: 0.0318 AC XY: 23049 AN XY: 725380

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00782

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0288

GnomAD4 genome AF: 0.0222 AC: 3386 AN: 152256 Hom.: 51 Cov.: 32 AF XY: 0.0212 AC XY: 1575 AN XY: 74452

Gnomad4 AFR AF: 0.00720

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0361

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0304 Hom.: 100

Bravo AF: 0.0206

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8192593; hg19: chr12-53901105;