chr12-53506843-C-G

Variant names:

• chr12-53506843-C-G
• NM_003717.4:c.275G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003717.4(NPFF):​c.275G>C​(p.Arg92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPFF NM_003717.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPFF	NM_003717.4	c.275G>C	p.Arg92Pro	missense_variant	Exon 3 of 3	ENST00000267017.4	NP_003708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPFF	ENST00000267017.4	c.275G>C	p.Arg92Pro	missense_variant	Exon 3 of 3	1	NM_003717.4	ENSP00000267017.3
ATF7-NPFF	ENST00000591834	c.*15G>C		3_prime_UTR_variant	Exon 13 of 13	5		ENSP00000466174.1
NPFF	ENST00000448979.4	n.515G>C		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452180 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721704

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.58
MutPred		0.26		Loss of MoRF binding (P = 0.0031);
MVP		0.48
MPC		1.0
ClinPred		0.99	D
GERP RS		-1.5
Varity_R		0.56
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53900627;