Genetic Variant NPLOC4:c.*1167A>C (chr17-81558092-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017921.4(NPLOC4):c.*1167A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 152,206 control chromosomes in the GnomAD database, including 31,600 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.64 ( 31550 hom., cov: 32)

Exomes 𝑓: 0.58 ( 50 hom. )

Consequence

NPLOC4
NM_017921.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.817

Publications

13 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4 link	c.*1167A>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000331134.11	NP_060391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPLOC4	ENST00000331134.11 link	c.*1167A>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_017921.4	ENSP00000331487.5
NPLOC4	ENST00000705719.1 link	c.*1167A>C		3_prime_UTR_variant	Exon 17 of 17			ENSP00000516165.1

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97428

AN:

151804

Hom.:

31516

Cov.:

show subpopulations

Gnomad AFR

AF:

0.641

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.544

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.646

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.667

Gnomad OTH

AF:

0.618

GnomAD4 exome

AF:

0.577

AC:

165

AN:

286

Hom.:

Cov.:

AF XY:

0.580

AC XY:

123

AN XY:

212

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.417

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.627

AC:

133

AN:

212

Other (OTH)

AF:

0.444

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.642

AC:

97506

AN:

151920

Hom.:

31550

Cov.:

AF XY:

0.643

AC XY:

47755

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.641

AC:

26555

AN:

41440

American (AMR)

AF:

0.529

AC:

8068

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.544

AC:

1886

AN:

3470

East Asian (EAS)

AF:

0.612

AC:

3151

AN:

5148

South Asian (SAS)

AF:

0.646

AC:

3108

AN:

4812

European-Finnish (FIN)

AF:

0.707

AC:

7466

AN:

10566

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.667

AC:

45317

AN:

67912

Other (OTH)

AF:

0.622

AC:

1314

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1707

3414

5120

6827

8534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.636

Hom.:

33143

Bravo

AF:

0.626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.95

(source)

DANN

Benign

0.30

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over