17-43953160-A-G

Position:

• chr17-43953160-A-G

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.218T>C​(p.Leu73Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,613,838 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (233 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (212 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0400

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=0.0034348965).
• BP6: Variant 17-43953160-A-G is Benign according to our data. Variant chr17-43953160-A-G is described in ClinVar as [Benign]. Clinvar id is 768889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYY	NM_001394028.1	c.218T>C	p.Leu73Pro	missense_variant	3/4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6	c.218T>C	p.Leu73Pro	missense_variant	6/7		NP_004151.4
PYY	NM_001394029.1	c.218T>C	p.Leu73Pro	missense_variant	3/3		NP_001380958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYY	ENST00000692052.1	c.218T>C	p.Leu73Pro	missense_variant	3/4		NM_001394028.1	ENSP00000509262.1
PYY	ENST00000360085.6	c.218T>C	p.Leu73Pro	missense_variant	6/7	1		ENSP00000353198.1
PYY	ENST00000592796.2	c.218T>C	p.Leu73Pro	missense_variant	3/3	1		ENSP00000467310.1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4585 AN: 152022 Hom.: 231 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.00784 AC: 1964 AN: 250582 Hom.: 75 AF XY: 0.00584 AC XY: 793 AN XY: 135764

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00318 AC: 4642 AN: 1461698 Hom.: 212 Cov.: 32 AF XY: 0.00273 AC XY: 1983 AN XY: 727166

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00660

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.00763

GnomAD4 genome AF: 0.0302 AC: 4589 AN: 152140 Hom.: 233 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74384

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00469 Hom.: 35

Bravo AF: 0.0342

ESP6500AA AF: 0.0911 AC: 401

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00941 AC: 1143

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Benign	0.024
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.051	T;D
Polyphen		0.0010	B;.
Vest4		0.28
MVP		0.13
MPC		1.2
ClinPred		0.022	T
GERP RS		1.7
Varity_R		0.20
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs61612861; hg19: chr17-42030528; COSMIC: COSV99080907;