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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017921.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPLOC4	NM_017921.4	MANE Select	c.*1167A>C	3_prime_UTR	Exon 17 of 17	NP_060391.2	Q8TAT6-1
NPLOC4	NM_001369698.1		c.*1167A>C	3_prime_UTR	Exon 17 of 17	NP_001356627.1
NPLOC4	NM_001438810.1		c.*1217A>C	3_prime_UTR	Exon 18 of 18	NP_001425739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPLOC4	ENST00000331134.11	TSL:1 MANE Select	c.*1167A>C		3_prime_UTR	Exon 17 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000705719.1		c.*1167A>C		3_prime_UTR	Exon 17 of 17	ENSP00000516165.1	A0A994J7H4

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over