17-43953188-A-C

Position:

chr17-43953188-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001394028.1(PYY):c.190T>G(p.Tyr64Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PYY
NM_001394028.1 missense, splice_region

Scores

Splicing: ADA: 0.06354

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.455

Variant links:

Genes affected

PYY (HGNC:9748): (peptide YY) This gene encodes a member of the neuropeptide Y (NPY) family of peptides. The encoded preproprotein is proteolytically processed to generate two alternative peptide products that differ in length by three amino acids. These peptides, secreted by endocrine cells in the gut, exhibit different binding affinities for each of the neuropeptide Y receptors. Binding of the encoded peptides to these receptors mediates regulation of pancreatic secretion, gut mobility and energy homeostasis. Rare variations in this gene could increase susceptibility to obesity and elevated serum levels of the encoded peptides may be associated with anorexia nervosa. [provided by RefSeq, Feb 2016]

PYY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYY	NM_001394028.1 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	3/4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	6/7		NP_004151.4	P10082-1
PYY	NM_001394029.1 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	3/3		NP_001380958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PYY	ENST00000692052.1 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	3/4		NM_001394028.1	ENSP00000509262.1	P10082-1
PYY	ENST00000360085.6 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	6/7	1		ENSP00000353198.1	P10082-1
PYY	ENST00000592796.2 link	c.190T>G	p.Tyr64Asp	missense_variant, splice_region_variant	3/3	1		ENSP00000467310.1	P10082-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150850

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249662

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135598

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000550

AC:

AN:

1453294

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723378

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000662

AC:

AN:

150982

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73816

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Jul 19, 2023

The c.190T>G (p.Y64D) alteration is located in exon 6 (coding exon 2) of the PYY gene. This alteration results from a T to G substitution at nucleotide position 190, causing the tyrosine (Y) at amino acid position 64 to be replaced by an aspartic acid (D). 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

0.048

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Benign

-0.40

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.4

D;.

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;.

Vest4

0.63

MutPred

0.83

Gain of ubiquitination at K66 (P = 0.0198);Gain of ubiquitination at K66 (P = 0.0198);

MVP

0.84

MPC

1.9

ClinPred

0.84

GERP RS

4.4

Varity_R

0.90

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.064

dbscSNV1_RF

Benign

0.36

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