17-43953444-C-G

Position:

• chr17-43953444-C-G

Variant summary

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

The NM_001394028.1(PYY):​c.40G>C​(p.Val14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.620

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=0.07233405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYY	NM_001394028.1	c.40G>C	p.Val14Leu	missense_variant	2/4	ENST00000692052.1	NP_001380957.1
PYY	NM_004160.6	c.40G>C	p.Val14Leu	missense_variant	5/7		NP_004151.4
PYY	NM_001394029.1	c.40G>C	p.Val14Leu	missense_variant	2/3		NP_001380958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYY	ENST00000692052.1	c.40G>C	p.Val14Leu	missense_variant	2/4		NM_001394028.1	ENSP00000509262.1
PYY	ENST00000360085.6	c.40G>C	p.Val14Leu	missense_variant	5/7	1		ENSP00000353198.1
PYY	ENST00000592796.2	c.40G>C	p.Val14Leu	missense_variant	2/3	1		ENSP00000467310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459558 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 14, 2023

The c.40G>C (p.V14L) alteration is located in exon 5 (coding exon 1) of the PYY gene. This alteration results from a G to C substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.55
DANN	Benign	0.62
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.065
Sift	Benign	1.0	T;.
Sift4G	Benign	0.93	T;T
Polyphen		0.020	B;.
Vest4		0.099
MutPred		0.42		Loss of catalytic residue at V14 (P = 0.0662);Loss of catalytic residue at V14 (P = 0.0662);
MVP		0.14
MPC		0.56
ClinPred		0.024	T
GERP RS		3.8
Varity_R		0.044
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42030812;