4-163325703-T-C

Position:

• chr4-163325703-T-C

Variant summary

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

The NM_000909.6(NPY1R):​c.755A>G​(p.Lys252Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,450,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NPY1R NM_000909.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

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 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=0.23973373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPY1R	NM_000909.6	c.755A>G	p.Lys252Arg	missense_variant	3/3	ENST00000296533.3	NP_000900.1
NPY1R	XM_005263031.5	c.755A>G	p.Lys252Arg	missense_variant	3/3		XP_005263088.1
NPY1R	XM_011532010.4	c.755A>G	p.Lys252Arg	missense_variant	3/3		XP_011530312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPY1R	ENST00000296533.3	c.755A>G	p.Lys252Arg	missense_variant	3/3	1	NM_000909.6	ENSP00000354652	P1
NPY1R	ENST00000509586.5	c.26A>G	p.Lys9Arg	missense_variant	4/4	2		ENSP00000427284
NPY1R	ENST00000512819.1	c.221A>G	p.Lys74Arg	missense_variant	4/4	4		ENSP00000421618
NPY1R	ENST00000504391.5	c.26A>G	p.Lys9Arg	missense_variant	5/5	5		ENSP00000422963

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450880 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722198

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 16, 2021

The c.755A>G (p.K252R) alteration is located in exon 3 (coding exon 2) of the NPY1R gene. This alteration results from a A to G substitution at nucleotide position 755, causing the lysine (K) at amino acid position 252 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	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.86	D;T;T;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.59	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.42	T;T;.;.
Polyphen		0.97	D;.;.;.
Vest4		0.063
MutPred		0.44		Gain of helix (P = 0.062);.;.;.;
MVP		0.61
MPC		0.55
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.23
gMVP		0.76

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: chr4-164246855; COSMIC: COSV99649064; COSMIC: COSV99649064;