chr4-163326157-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000909.6(NPY1R):​c.398T>A​(p.Leu133His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

NPY1R
NM_000909.6 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPY1RNM_000909.6 linkc.398T>A p.Leu133His missense_variant Exon 2 of 3 ENST00000296533.3 NP_000900.1 P25929
NPY1RXM_005263031.5 linkc.398T>A p.Leu133His missense_variant Exon 2 of 3 XP_005263088.1 P25929
NPY1RXM_011532010.4 linkc.398T>A p.Leu133His missense_variant Exon 2 of 3 XP_011530312.1 P25929

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPY1RENST00000296533.3 linkc.398T>A p.Leu133His missense_variant Exon 2 of 3 1 NM_000909.6 ENSP00000354652.2 P25929

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.398T>A (p.L133H) alteration is located in exon 2 (coding exon 1) of the NPY1R gene. This alteration results from a T to A substitution at nucleotide position 398, causing the leucine (L) at amino acid position 133 to be replaced by a histidine (H). 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D
M_CAP
Uncertain
0.089
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Uncertain
-0.00080
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.64
Loss of stability (P = 0.0781);
MVP
0.85
MPC
1.8
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.90
gMVP
0.77

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: chr4-164247309; API