12-53506856-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 71 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 86 hom. )

Consequence

NPFF
NM_003717.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.829

Publications

6 publications found

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]

NPFF links:

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]

ATF7-NPFF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003717.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPFF	NM_003717.4	MANE Select	c.262T>C	p.Trp88Arg	missense	Exon 3 of 3	NP_003708.1	O15130-1
NPFF	NM_001320296.2		c.271T>C	p.Trp91Arg	missense	Exon 2 of 2	NP_001307225.1	O15130-2
ATF7-NPFF	NM_001366559.1		c.*2T>C		3_prime_UTR	Exon 13 of 13	NP_001353488.1	K7ELQ4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPFF	ENST00000267017.4	TSL:1 MANE Select	c.262T>C	p.Trp88Arg	missense	Exon 3 of 3	ENSP00000267017.3	O15130-1
ATF7-NPFF	ENST00000591834.1	TSL:5	c.*2T>C		3_prime_UTR	Exon 13 of 13	ENSP00000466174.1	K7ELQ4
NPFF	ENST00000448979.4	TSL:1	n.502T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2901

AN:

152140

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00728

AC:

1769

AN:

242936

AF XY:

0.00584

show subpopulations

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 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.:

Cov.:

AF XY:

0.00266

AC XY:

1918

AN XY:

721782

show subpopulations

African (AFR)

AF:

0.0597

AC:

1978

AN:

33158

American (AMR)

AF:

0.00248

AC:

108

AN:

43500

Ashkenazi Jewish (ASJ)

AF:

0.0000788

AC:

AN:

25380

East Asian (EAS)

AF:

0.0293

AC:

1162

AN:

39614

South Asian (SAS)

AF:

0.00136

AC:

115

AN:

84810

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000494

AC:

547

AN:

1107236

Other (OTH)

AF:

0.00502

AC:

301

AN:

59990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

206

412

617

823

1029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2904

AN:

152258

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1321

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0629

AC:

2614

AN:

41528

American (AMR)

AF:

0.00471

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0279

AC:

145

AN:

5192

South Asian (SAS)

AF:

0.00228

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.0123

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

145

290

435

580

725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.0209

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0631

AC:

278

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00830

AC:

1007

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.7

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0085

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.097

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

PhyloP100

-0.83

PrimateAI

Benign

0.26

PROVEAN

Benign

4.8

REVEL

Benign

0.044

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.031

MutPred

0.10

Loss of catalytic residue at P91 (P = 0.0269)

MVP

0.072

MPC

0.40

ClinPred

0.0013

GERP RS

-2.8

Varity_R

0.049

gMVP

0.018

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over