chr4-163326157-A-T

Variant names:

• chr4-163326157-A-T
• NM_000909.6:c.398T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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 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
NPY1R	NM_000909.6	c.398T>A	p.Leu133His	missense_variant	Exon 2 of 3	ENST00000296533.3	NP_000900.1
NPY1R	XM_005263031.5	c.398T>A	p.Leu133His	missense_variant	Exon 2 of 3		XP_005263088.1
NPY1R	XM_011532010.4	c.398T>A	p.Leu133His	missense_variant	Exon 2 of 3		XP_011530312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPY1R	ENST00000296533.3	c.398T>A	p.Leu133His	missense_variant	Exon 2 of 3	1	NM_000909.6	ENSP00000354652.2

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

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;