chr4-163325749-G-A

Position:

• chr4-163325749-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000909.6(NPY1R):​c.709C>T​(p.Arg237Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,588,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NPY1R NM_000909.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39

Genes affected

NPY1R (HGNC:7956): (neuropeptide Y receptor Y1) This gene belongs to the G-protein-coupled receptor superfamily. The encoded transmembrane protein mediates the function of neuropeptide Y (NPY), a neurotransmitter, and peptide YY (PYY), a gastrointestinal hormone. The encoded receptor undergoes fast agonist-induced internalization through clathrin-coated pits and is subsequently recycled back to the cell membrane. Activation of Y1 receptors may result in mobilization of intracellular calcium and inhibition of adenylate cyclase activity. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033162236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPY1R	NM_000909.6	c.709C>T	p.Arg237Cys	missense_variant	3/3	ENST00000296533.3	NP_000900.1
NPY1R	XM_005263031.5	c.709C>T	p.Arg237Cys	missense_variant	3/3		XP_005263088.1
NPY1R	XM_011532010.4	c.709C>T	p.Arg237Cys	missense_variant	3/3		XP_011530312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPY1R	ENST00000296533.3	c.709C>T	p.Arg237Cys	missense_variant	3/3	1	NM_000909.6	ENSP00000354652	P1
NPY1R	ENST00000512819.1	c.175C>T	p.Arg59Cys	missense_variant	4/4	4		ENSP00000421618
NPY1R	ENST00000504391.5	c.-21C>T		5_prime_UTR_variant	5/5	5		ENSP00000422963
NPY1R	ENST00000509586.5	c.-21C>T		5_prime_UTR_variant	4/4	2		ENSP00000427284

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000307 AC: 73 AN: 237618 Hom.: 0 AF XY: 0.000302 AC XY: 39 AN XY: 129076

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.000267

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 251 AN: 1436462 Hom.: 0 Cov.: 26 AF XY: 0.000184 AC XY: 132 AN XY: 715554

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.0000911

Gnomad4 ASJ exome AF: 0.00381

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.000177

Gnomad4 NFE exome AF: 0.0000837

Gnomad4 OTH exome AF: 0.000402

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151980 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74226

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000280 AC: 34

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

Jul 19, 2022

The c.709C>T (p.R237C) alteration is located in exon 3 (coding exon 2) of the NPY1R gene. This alteration results from a C to T substitution at nucleotide position 709, causing the arginine (R) at amino acid position 237 to be replaced by a cysteine (C). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;N
REVEL	Benign	0.26
Sift	Benign	0.19	T;T
Sift4G	Benign	0.098	T;.
Polyphen		0.068	B;.
Vest4		0.71
MVP		0.72
MPC		1.1
ClinPred		0.054	T
GERP RS		5.8
Varity_R		0.50
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201792729; hg19: chr4-164246901;