chr4-163350713-T-C

Variant names:

• chr4-163350713-T-C
• rs1322149205
• NM_006174.4:c.440T>C

Variant summary

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

The NM_006174.4(NPY5R):​c.440T>C​(p.Ile147Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPY5R NM_006174.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

NPY5R (HGNC:7958): (neuropeptide Y receptor Y5) The protein encoded by this gene is a receptor for neuropeptide Y and peptide YY. The encoded protein appears to be involved in regulating food intake, with defects in this gene being associated with eating disorders. Also, the encoded protein is involved in a pathway that protects neuroblastoma cells from chemotherapy-induced cell death, providing a possible therapeutic target against neuroblastoma. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Nov 2015]

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=0.18205944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPY5R	NM_006174.4	c.440T>C	p.Ile147Thr	missense_variant	Exon 4 of 4	ENST00000338566.8	NP_006165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPY5R	ENST00000338566.8	c.440T>C	p.Ile147Thr	missense_variant	Exon 4 of 4	1	NM_006174.4	ENSP00000339377.3
NPY5R	ENST00000506953.1	c.440T>C	p.Ile147Thr	missense_variant	Exon 1 of 1	6		ENSP00000423474.1
NPY5R	ENST00000515560.1	c.440T>C	p.Ile147Thr	missense_variant	Exon 4 of 4	2		ENSP00000423917.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440T>C (p.I147T) alteration is located in exon 4 (coding exon 1) of the NPY5R gene. This alteration results from a T to C substitution at nucleotide position 440, causing the isoleucine (I) at amino acid position 147 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.085	T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	.;.;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.29	T;T;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.30
MutPred		0.64		Gain of disorder (P = 0.0086);Gain of disorder (P = 0.0086);Gain of disorder (P = 0.0086);
MVP		0.73
MPC		0.29
ClinPred		0.34	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.24

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: rs1322149205; hg19: chr4-164271865;