Genetic Variant NPLOC4:p.Ala579Val (chr17-81559350-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017921.4(NPLOC4):c.1736C>T(p.Ala579Val) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,455,262 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NPLOC4
NM_017921.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

Publications

1 publications found

Variant links:

Genes affected

NPLOC4 (HGNC:18261): (NPL4 homolog, ubiquitin recognition factor) Predicted to enable ATPase binding activity; ubiquitin binding activity; and ubiquitin protein ligase binding activity. Predicted to contribute to K48-linked polyubiquitin modification-dependent protein binding activity and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in negative regulation of RIG-I signaling pathway; negative regulation of type I interferon production; and proteolysis involved in cellular protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]

NPLOC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16352117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4 link	c.1736C>T	p.Ala579Val	missense_variant	Exon 17 of 17	ENST00000331134.11	NP_060391.2	Q8TAT6-1A0A024R8R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPLOC4	ENST00000331134.11 link	c.1736C>T	p.Ala579Val	missense_variant	Exon 17 of 17	1	NM_017921.4	ENSP00000331487.5		Q8TAT6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000429

AC:

AN:

233260

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1455262

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

43702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39486

South Asian (SAS)

AF:

0.00

AC:

AN:

85042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52426

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1109456

Other (OTH)

AF:

0.00

AC:

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 28, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1736C>T (p.A579V) alteration is located in exon 17 (coding exon 17) of the NPLOC4 gene. This alteration results from a C to T substitution at nucleotide position 1736, causing the alanine (A) at amino acid position 579 to be replaced by a valine (V). 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

0.086

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.033

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

M_CAP

Benign

0.0048

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

PhyloP100

5.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.94

REVEL

Benign

0.057

Sift

Benign

0.29

Sift4G

Benign

0.64

Polyphen

0.0010

Vest4

0.051

MutPred

0.34

Gain of catalytic residue at A579 (P = 0.0643);

MVP

0.30

MPC

0.013

ClinPred

0.18

GERP RS

5.2

Varity_R

0.099

gMVP

0.28

Mutation Taster

=77/23

polymorphism

(source)

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

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17-81559350-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over