chr17-43953188-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150850

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249662

AF XY:

0.00000737

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33104

American (AMR)

AF:

0.00

AC:

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39136

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000362

AC:

AN:

1105882

Other (OTH)

AF:

0.00

AC:

AN:

59890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000018), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41174

American (AMR)

AF:

0.0000658

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5008

South Asian (SAS)

AF:

0.00

AC:

AN:

4646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67710

Other (OTH)

AF:

0.00

AC:

AN:

2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.46

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

Mutation Taster

=35/65

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr17-43953188-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over