chr12-53506843-C-G

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 š‘“: 6.9e-7 ( 0 hom. )

Consequence

NPFF
NM_003717.4 missense

Scores

1
5
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0520
Variant links:
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]

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ACMG classification

Classification made for transcript

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
NPFFNM_003717.4 linkc.275G>C p.Arg92Pro missense_variant Exon 3 of 3 ENST00000267017.4 NP_003708.1 O15130-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPFFENST00000267017.4 linkc.275G>C p.Arg92Pro missense_variant Exon 3 of 3 1 NM_003717.4 ENSP00000267017.3 O15130-1
ATF7-NPFFENST00000591834 linkc.*15G>C 3_prime_UTR_variant Exon 13 of 13 5 ENSP00000466174.1 K7ELQ4
NPFFENST00000448979.4 linkn.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
show subpopulations
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; API