17-43953335-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394028.1(PYY):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A50A) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PYY
NM_001394028.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25084704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYY	NM_001394028.1 link	c.149C>T	p.Ala50Val	missense_variant	Exon 2 of 4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6 link	c.149C>T	p.Ala50Val	missense_variant	Exon 5 of 7		NP_004151.4	P10082-1
PYY	NM_001394029.1 link	c.149C>T	p.Ala50Val	missense_variant	Exon 2 of 3		NP_001380958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYY	ENST00000692052.1 link	c.149C>T	p.Ala50Val	missense_variant	Exon 2 of 4		NM_001394028.1	ENSP00000509262.1	P10082-1
PYY	ENST00000360085.6 link	c.149C>T	p.Ala50Val	missense_variant	Exon 5 of 7	1		ENSP00000353198.1	P10082-1
PYY	ENST00000592796.2 link	c.149C>T	p.Ala50Val	missense_variant	Exon 2 of 3	1		ENSP00000467310.1	P10082-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246240

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000640

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

AF:

6.85e-7

AC:

AN:

1460648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726648

show subpopulations

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

African (AFR)

AF:

0.0000299

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111596

Other (OTH)

AF:

0.00

AC:

AN:

60290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

Jan 04, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.149C>T (p.A50V) alteration is located in exon 5 (coding exon 1) of the PYY gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). 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

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

0.071

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.77

PhyloP100

3.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

N;.

REVEL

Benign

0.080

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.015

D;D

Polyphen

0.47

P;.

Vest4

0.21

MutPred

0.48

Loss of disorder (P = 0.092);Loss of disorder (P = 0.092);

MVP

0.47

MPC

1.1

ClinPred

0.67

GERP RS

3.7

Varity_R

0.25

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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17-43953335-G-A

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