NM_001394028.1:c.178A>G

Variant names:

• chr17-43953306-T-C
• rs768312331
• NM_001394028.1:c.178A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001394028.1(PYY):​c.178A>G​(p.Thr60Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T60P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PYY NM_001394028.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394028.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYY	NM_001394028.1	MANE Select	c.178A>G	p.Thr60Ala	missense	Exon 2 of 4	NP_001380957.1	P10082-1
	PYY	NM_004160.6		c.178A>G	p.Thr60Ala	missense	Exon 5 of 7	NP_004151.4	P10082-1
	PYY	NM_001394029.1		c.178A>G	p.Thr60Ala	missense	Exon 2 of 3	NP_001380958.1	P10082-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYY	ENST00000692052.1	MANE Select	c.178A>G	p.Thr60Ala	missense	Exon 2 of 4	ENSP00000509262.1	P10082-1
	PYY	ENST00000360085.6	TSL:1	c.178A>G	p.Thr60Ala	missense	Exon 5 of 7	ENSP00000353198.1	P10082-1
	PYY	ENST00000592796.2	TSL:1	c.178A>G	p.Thr60Ala	missense	Exon 2 of 3	ENSP00000467310.1	P10082-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 245214 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460196 Hom.: 0 Cov.: 49 AF XY: 0.00000551 AC XY: 4 AN XY: 726402

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111284

Other (OTH) AF: 0.0000166 AC: 1 AN: 60290

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.27	T
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.88		Loss of phosphorylation at T60 (P = 0.1305)
MVP		0.82
MPC		1.3
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.73
gMVP		0.66
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs768312331; hg19: chr17-42030674;