17-43941606-C-T

Position:

chr17-43941606-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002722.5(PPY):c.49G>A(p.Val17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PPY
NM_002722.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.258

Variant links:

Genes affected

PPY (HGNC:9327): (pancreatic polypeptide) This gene encodes a member of the neuropeptide Y (NPY) family of peptides. The encoded 95 aa preproprotein is synthesized in the pancreatic islets of Langerhans and proteolytically processed to generate two peptide products. These products include the active pancreatic hormone of 36 aa and an icosapeptide of unknown function. This hormone acts as a regulator of pancreatic and gastrointestinal functions and may be important in the regulation of food intake. Plasma level of this hormone has been shown to be reduced in conditions associated with increased food intake and elevated in anorexia nervosa. In addition, infusion of this hormone in obese rodents has shown to decrease weight gain. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

PPY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15953013).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPY	NM_002722.5 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/4	ENST00000225992.8	NP_002713.1
PPY	NM_001319209.2 linkuse as main transcript	c.67G>A	p.Val23Met	missense_variant	2/4		NP_001306138.1
PPY	XM_011524978.4 linkuse as main transcript	c.76G>A	p.Val26Met	missense_variant	2/4		XP_011523280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPY	ENST00000225992.8 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/4	1	NM_002722.5	ENSP00000225992	P1	P01298-1
PPY	ENST00000587006.2 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	1/3	3		ENSP00000465711
PPY	ENST00000591228.4 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/4	5		ENSP00000466009	P1	P01298-1
PPY	ENST00000591703.5 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant, NMD_transcript_variant	2/4	5		ENSP00000466546

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250570

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135490

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461040

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726802

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.49G>A (p.V17M) alteration is located in exon 2 (coding exon 1) of the PPY gene. This alteration results from a G to A substitution at nucleotide position 49, causing the valine (V) at amino acid position 17 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.71

.;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.0

N;.;.

REVEL

Benign

0.022

Sift

Benign

0.13

T;.;.

Sift4G

Benign

0.13

T;T;T

Polyphen

0.90

P;P;.

Vest4

0.33

MutPred

0.34

Loss of catalytic residue at V17 (P = 0.2687);Loss of catalytic residue at V17 (P = 0.2687);Loss of catalytic residue at V17 (P = 0.2687);

MVP

0.27

MPC

0.25

ClinPred

0.90

GERP RS

2.2

Varity_R

0.083

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over