17-47601712-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006310.4(NPEPPS):c.1705G>A(p.Val569Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NPEPPS NM_006310.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

NPEPPS (HGNC:7900): (aminopeptidase puromycin sensitive) This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkaphalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NPEPPS
• BP4: Computational evidence support a benign effect (MetaRNN=0.067359686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPEPPS	NM_006310.4	c.1705G>A	p.Val569Ile	missense_variant	15/23	ENST00000322157.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPEPPS	ENST00000322157.9	c.1705G>A	p.Val569Ile	missense_variant	15/23	1	NM_006310.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.1705G>A (p.V569I) alteration is located in exon 15 (coding exon 15) of the NPEPPS gene. This alteration results from a G to A substitution at nucleotide position 1705, causing the valine (V) at amino acid position 569 to be replaced by an isoleucine (I). 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	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	17
Dann	Benign	0.91
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.62	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.096
Sift	Benign	0.31	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0060	B;B
Vest4		0.051
MutPred		0.46		.;Gain of sheet (P = 0.0827);
MVP		0.11
MPC		0.47
ClinPred		0.18	T
GERP RS		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.17

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: chr17-45679078;