rs1058046

Positions:

• chr17-43953163-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001394028.1(PYY):​c.215C>G​(p.Thr72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,580 control chromosomes in the GnomAD database, including 349,468 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.59 (27749 hom., cov: 32)
  • Exomes 𝑓: 0.66 (321719 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.168196E-6).
• BP6: Variant 17-43953163-G-C is Benign according to our data. Variant chr17-43953163-G-C is described in ClinVar as [Benign]. Clinvar id is 1178202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYY	NM_001394028.1	c.215C>G	p.Thr72Arg	missense_variant	3/4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6	c.215C>G	p.Thr72Arg	missense_variant	6/7		NP_004151.4
PYY	NM_001394029.1	c.215C>G	p.Thr72Arg	missense_variant	3/3		NP_001380958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYY	ENST00000692052.1	c.215C>G	p.Thr72Arg	missense_variant	3/4		NM_001394028.1	ENSP00000509262	P1
PYY	ENST00000360085.6	c.215C>G	p.Thr72Arg	missense_variant	6/7	1		ENSP00000353198	P1
PYY	ENST00000592796.2	c.215C>G	p.Thr72Arg	missense_variant	3/3	1		ENSP00000467310

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90306 AN: 151918 Hom.: 27739 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.583

GnomAD3 exomes AF: 0.629 AC: 157612 AN: 250384 Hom.: 51111 AF XY: 0.641 AC XY: 86986 AN XY: 135666

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.634

Gnomad EAS exome AF: 0.334

Gnomad SAS exome AF: 0.737

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.671

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.659 AC: 963228 AN: 1461544 Hom.: 321719 Cov.: 68 AF XY: 0.662 AC XY: 481302 AN XY: 727082

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.639

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.736

Gnomad4 FIN exome AF: 0.691

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.594 AC: 90328 AN: 152036 Hom.: 27749 Cov.: 32 AF XY: 0.598 AC XY: 44403 AN XY: 74310

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.731

Gnomad4 FIN AF: 0.701

Gnomad4 NFE AF: 0.669

Gnomad4 OTH AF: 0.583

Alfa AF: 0.649 Hom.: 24434

Bravo AF: 0.574

TwinsUK AF: 0.669 AC: 2481

ALSPAC AF: 0.673 AC: 2593

ESP6500AA AF: 0.452 AC: 1988

ESP6500EA AF: 0.665 AC: 5717

ExAC AF: 0.628 AC: 76200

Asia WGS AF: 0.529 AC: 1844 AN: 3478

EpiCase AF: 0.666

EpiControl AF: 0.660

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 15983231) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.5
DANN	Benign	0.83
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0000042	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.014
Sift	Benign	0.089	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.089	B;.
Vest4		0.17
MPC		0.58
ClinPred		0.0070	T
GERP RS		1.6
Varity_R		0.078
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1058046; hg19: chr17-42030531; COSMIC: COSV63970394;