rs5578

Variant names:

• chr4-163325337-T-G
• rs5578
• NM_000909.6:c.1121A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.42
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -16 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 VariationId is 774176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000909.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPY1R	NM_000909.6	MANE Select	c.1121A>C	p.Lys374Thr	missense	Exon 3 of 3	NP_000900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPY1R	ENST00000296533.3	TSL:1 MANE Select	c.1121A>C	p.Lys374Thr	missense	Exon 3 of 3	ENSP00000354652.2
	NPY1R	ENST00000509586.5	TSL:2	c.392A>C	p.Lys131Thr	missense	Exon 4 of 4	ENSP00000427284.1
	NPY1R	ENST00000504391.5	TSL:5	c.*199A>C		downstream_gene	N/A	ENSP00000422963.1

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

GnomAD2 exomes AF: 0.00507 AC: 1263 AN: 248876 AF XY: 0.00528

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 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

African (AFR) AF: 0.000816 AC: 27 AN: 33106

American (AMR) AF: 0.00506 AC: 223 AN: 44088

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 333 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00320 AC: 274 AN: 85624

European-Finnish (FIN) AF: 0.00245 AC: 131 AN: 53362

Middle Eastern (MID) AF: 0.00784 AC: 45 AN: 5742

European-Non Finnish (NFE) AF: 0.00715 AC: 7944 AN: 1111184

Other (OTH) AF: 0.00623 AC: 375 AN: 60214

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

African (AFR) AF: 0.00142 AC: 59 AN: 41590

American (AMR) AF: 0.00582 AC: 89 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4834

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00726 AC: 494 AN: 68014

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00687 Hom.: 13

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D
Sift4G	Benign	0.21	T
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
Mutation Taster		=86/14	polymorphism

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