dbSNP rs3754090: NVL:p.Leu246Leu (chr1-224305044-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_002533.4(NVL):c.738G>A(p.Leu246Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 1,613,154 control chromosomes in the GnomAD database, including 694,986 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 0.84 ( 56115 hom., cov: 31)

Exomes 𝑓: 0.93 ( 638871 hom. )

Consequence

NVL
NM_002533.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Publications

22 publications found

Variant links:

Genes affected

NVL (HGNC:8070): (nuclear VCP like) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) superfamily. Multiple transcript variants encoding different isoforms have been found for this gene. Two encoded proteins, described as major and minor isoforms, have been localized to distinct regions of the nucleus. The largest encoded protein (major isoform) has been localized to the nucleolus and shown to participate in ribosome biosynthesis (PMID: 15469983, 16782053), while the minor isoform has been localized to the nucleoplasmin. [provided by RefSeq, Aug 2011]

NVL links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.075).

BP7

Synonymous conserved (PhyloP=0.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NVL	NM_002533.4 link	c.738G>A	p.Leu246Leu	synonymous_variant	Exon 7 of 23	ENST00000281701.11	NP_002524.2	O15381-1B4DF43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NVL	ENST00000281701.11 link	c.738G>A	p.Leu246Leu	synonymous_variant	Exon 7 of 23	1	NM_002533.4	ENSP00000281701.6		O15381-1

Frequencies

GnomAD3 genomes

AF:

0.844

AC:

128313

AN:

152060

Hom.:

56089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.911

Gnomad AMR

AF:

0.926

Gnomad ASJ

AF:

0.927

Gnomad EAS

AF:

0.903

Gnomad SAS

AF:

0.921

Gnomad FIN

AF:

0.977

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.945

Gnomad OTH

AF:

0.866

GnomAD2 exomes

AF:

0.921

AC:

230815

AN:

250744

AF XY:

0.927

show subpopulations

Gnomad AFR exome

AF:

0.577

Gnomad AMR exome

AF:

0.961

Gnomad ASJ exome

AF:

0.932

Gnomad EAS exome

AF:

0.899

Gnomad FIN exome

AF:

0.972

Gnomad NFE exome

AF:

0.946

Gnomad OTH exome

AF:

0.934

GnomAD4 exome

AF:

0.933

AC:

1363549

AN:

1460976

Hom.:

638871

Cov.:

AF XY:

0.934

AC XY:

679003

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.580

AC:

19401

AN:

33438

American (AMR)

AF:

0.955

AC:

42629

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.933

AC:

24340

AN:

26100

East Asian (EAS)

AF:

0.917

AC:

36383

AN:

39678

South Asian (SAS)

AF:

0.930

AC:

80049

AN:

86090

European-Finnish (FIN)

AF:

0.973

AC:

51748

AN:

53204

Middle Eastern (MID)

AF:

0.933

AC:

5380

AN:

5768

European-Non Finnish (NFE)

AF:

0.943

AC:

1048222

AN:

1111686

Other (OTH)

AF:

0.917

AC:

55397

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4293

8586

12879

17172

21465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.844

AC:

128383

AN:

152178

Hom.:

56115

Cov.:

AF XY:

0.848

AC XY:

63085

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.587

AC:

24325

AN:

41464

American (AMR)

AF:

0.927

AC:

14172

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.927

AC:

3215

AN:

3470

East Asian (EAS)

AF:

0.903

AC:

4681

AN:

5184

South Asian (SAS)

AF:

0.923

AC:

4442

AN:

4814

European-Finnish (FIN)

AF:

0.977

AC:

10371

AN:

10616

Middle Eastern (MID)

AF:

0.929

AC:

273

AN:

294

European-Non Finnish (NFE)

AF:

0.944

AC:

64241

AN:

68016

Other (OTH)

AF:

0.868

AC:

1834

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

827

1654

2482

3309

4136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.913

Hom.:

100833

Bravo

AF:

0.829

Asia WGS

AF:

0.889

AC:

3090

AN:

3478

EpiCase

AF:

0.949

EpiControl

AF:

0.949

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.4

(source)

DANN

Benign

0.63

PhyloP100

0.21

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=99/1

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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rs3754090

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