Variant chr17-43941213-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_002722.5(PPY):c.193T>A(p.Tyr65Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PPY
NM_002722.5 missense, splice_region

Scores

Splicing: ADA: 0.1749

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

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:

PPY (HGNC:):

PPY links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a modified_residue Tyrosine amide (size 0) in uniprot entity PAHO_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPY	NM_002722.5 linkuse as main transcript	c.193T>A	p.Tyr65Asn	missense_variant, splice_region_variant	3/4	ENST00000225992.8	NP_002713.1	P01298-1
PPY	NM_001319209.2 linkuse as main transcript	c.211T>A	p.Tyr71Asn	missense_variant, splice_region_variant	3/4		NP_001306138.1
PPY	XM_011524978.4 linkuse as main transcript	c.220T>A	p.Tyr74Asn	missense_variant, splice_region_variant	3/4		XP_011523280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPY	ENST00000225992.8 linkuse as main transcript	c.193T>A	p.Tyr65Asn	missense_variant, splice_region_variant	3/4	1	NM_002722.5	ENSP00000225992.3		P01298-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000641

AC:

AN:

155916

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 20, 2023

The c.193T>A (p.Y65N) alteration is located in exon 3 (coding exon 2) of the PPY gene. This alteration results from a T to A substitution at nucleotide position 193, causing the tyrosine (Y) at amino acid position 65 to be replaced by an asparagine (N). 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

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

.;D;T

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.36

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.4

D;.;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.75

MutPred

0.80

Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);.;

MVP

0.83

MPC

1.1

ClinPred

0.97

GERP RS

3.8

Varity_R

0.83

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.17

dbscSNV1_RF

Benign

0.52

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