17-43953163-G-C

Variant names:

• chr17-43953163-G-C
• rs1058046
• NM_001394028.1:c.215C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 46 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PYY	NM_001394028.1	c.215C>G	p.Thr72Arg	missense_variant	Exon 3 of 4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6	c.215C>G	p.Thr72Arg	missense_variant	Exon 6 of 7		NP_004151.4
PYY	NM_001394029.1	c.215C>G	p.Thr72Arg	missense_variant	Exon 3 of 3		NP_001380958.1

Ensembl

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

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

GnomAD2 exomes AF: 0.629 AC: 157612 AN: 250384 AF XY: 0.641

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 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

African (AFR) AF: 0.439 AC: 14702 AN: 33468

American (AMR) AF: 0.590 AC: 26364 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 16696 AN: 26132

East Asian (EAS) AF: 0.318 AC: 12614 AN: 39698

South Asian (SAS) AF: 0.736 AC: 63503 AN: 86238

European-Finnish (FIN) AF: 0.691 AC: 36888 AN: 53390

Middle Eastern (MID) AF: 0.601 AC: 3462 AN: 5764

European-Non Finnish (NFE) AF: 0.675 AC: 750267 AN: 1111772

Other (OTH) AF: 0.641 AC: 38732 AN: 60384

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

African (AFR) AF: 0.457 AC: 18935 AN: 41462

American (AMR) AF: 0.597 AC: 9128 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2231 AN: 3466

East Asian (EAS) AF: 0.325 AC: 1678 AN: 5156

South Asian (SAS) AF: 0.731 AC: 3522 AN: 4816

European-Finnish (FIN) AF: 0.701 AC: 7423 AN: 10594

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45468 AN: 67930

Other (OTH) AF: 0.583 AC: 1232 AN: 2114

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.038
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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