Variant 17-81604567-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017921.4(NPLOC4):c.815C>T(p.Ala272Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,612,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

NPLOC4
NM_017921.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.61

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:

Genome browser will be placed here

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, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4 link	c.815C>T	p.Ala272Val	missense_variant	Exon 8 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.815C>T	p.Ala272Val	missense_variant	Exon 8 of 17	1	NM_017921.4	ENSP00000331487.5		Q8TAT6-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000892

AC:

AN:

246624

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133768

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 SAS exome

AF:

0.000365

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000637

AC:

AN:

1460058

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

726230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000407

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.815C>T (p.A272V) alteration is located in exon 8 (coding exon 8) of the NPLOC4 gene. This alteration results from a C to T substitution at nucleotide position 815, causing the alanine (A) at amino acid position 272 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

0.31

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

-0.098

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.52

Sift

Benign

0.037

D;.

Sift4G

Uncertain

0.042

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.89

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.76

MPC

2.0

ClinPred

0.60

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over