4-163325337-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000909.6(NPY1R):c.1121A>C(p.Lys374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,611,318 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (43 hom.)
• Consequence: NPY1R NM_000909.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005621642).
• BP6: Variant 4-163325337-T-G is Benign according to our data. Variant chr4-163325337-T-G is described in ClinVar as [Benign]. Clinvar id is 774176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPY1R	NM_000909.6	c.1121A>C	p.Lys374Thr	missense_variant	3/3	ENST00000296533.3
NPY1R	XM_005263031.5	c.1121A>C	p.Lys374Thr	missense_variant	3/3
NPY1R	XM_011532010.4	c.1121A>C	p.Lys374Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPY1R	ENST00000296533.3	c.1121A>C	p.Lys374Thr	missense_variant	3/3	1	NM_000909.6	P1
NPY1R	ENST00000509586.5	c.392A>C	p.Lys131Thr	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 731 AN: 152230 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00507 AC: 1263 AN: 248876 Hom.: 10 AF XY: 0.00528 AC XY: 710 AN XY: 134502

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00315

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00703

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.00641 AC: 9352 AN: 1458970 Hom.: 43 Cov.: 31 AF XY: 0.00634 AC XY: 4599 AN XY: 725712

Gnomad4 AFR exome AF: 0.000816

Gnomad4 AMR exome AF: 0.00506

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00715

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152348 Hom.: 8 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74516

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00726

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00755 Hom.: 11

Bravo AF: 0.00488

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00467 AC: 567

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0100

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.089	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.79	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.29	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.21	T;D
Polyphen		0.42	B;.
Vest4		0.33
MVP		0.71
MPC		0.99
ClinPred		0.024	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs5578; hg19: chr4-164246489; COSMIC: COSV56714232; COSMIC: COSV56714232;