17-43953169-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394028.1(PYY):c.209C>G(p.Pro70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P70L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08573803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYY	NM_001394028.1	c.209C>G	p.Pro70Arg	missense_variant	3/4	ENST00000692052.1
PYY	NM_004160.6	c.209C>G	p.Pro70Arg	missense_variant	6/7
PYY	NM_001394029.1	c.209C>G	p.Pro70Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYY	ENST00000692052.1	c.209C>G	p.Pro70Arg	missense_variant	3/4		NM_001394028.1	P1
PYY	ENST00000360085.6	c.209C>G	p.Pro70Arg	missense_variant	6/7	1		P1
PYY	ENST00000592796.2	c.209C>G	p.Pro70Arg	missense_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000679 AC: 17 AN: 250398 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135718

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461666 Hom.: 0 Cov.: 49 AF XY: 0.0000399 AC XY: 29 AN XY: 727150

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.209C>G (p.P70R) alteration is located in exon 6 (coding exon 2) of the PYY gene. This alteration results from a C to G substitution at nucleotide position 209, causing the proline (P) at amino acid position 70 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Benign	0.040
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.042	D;T
Polyphen		0.78	P;.
Vest4		0.14
MutPred		0.30		Gain of MoRF binding (P = 0.002);Gain of MoRF binding (P = 0.002);
MVP		0.28
MPC		0.99
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.16
gMVP		0.24

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: rs770520813; hg19: chr17-42030537;