rs267606994

chr17-43953299-T-Cchr17-43953299-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001394028.1(PYY):c.185A>G(p.Gln62Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q62P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYY	NM_001394028.1	c.185A>G	p.Gln62Arg	missense_variant	2/4	ENST00000692052.1
PYY	NM_004160.6	c.185A>G	p.Gln62Arg	missense_variant	5/7
PYY	NM_001394029.1	c.185A>G	p.Gln62Arg	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYY	ENST00000692052.1	c.185A>G	p.Gln62Arg	missense_variant	2/4		NM_001394028.1	P1
PYY	ENST00000360085.6	c.185A>G	p.Gln62Arg	missense_variant	5/7	1		P1
PYY	ENST00000592796.2	c.185A>G	p.Gln62Arg	missense_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244558 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1459920 Hom.: 0 Cov.: 50 AF XY: 0.00000138 AC XY: 1 AN XY: 726222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.75		Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);
MVP		0.68
MPC		0.69
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267606994; hg19: chr17-42030667;