rs3754090

Variant names:

• chr1-224305044-C-T
• rs3754090
• NM_002533.4:c.738G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 22 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002533.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	NM_002533.4	MANE Select	c.738G>A	p.Leu246Leu	synonymous	Exon 7 of 23	NP_002524.2
	NVL	NM_001243147.2		c.465G>A	p.Leu155Leu	synonymous	Exon 6 of 22	NP_001230076.1
	NVL	NM_206840.3		c.420G>A	p.Leu140Leu	synonymous	Exon 6 of 22	NP_996671.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	ENST00000281701.11	TSL:1 MANE Select	c.738G>A	p.Leu246Leu	synonymous	Exon 7 of 23	ENSP00000281701.6
	NVL	ENST00000391875.6	TSL:1	c.420G>A	p.Leu140Leu	synonymous	Exon 6 of 22	ENSP00000375747.2
	NVL	ENST00000469075.5	TSL:2	c.465G>A	p.Leu155Leu	synonymous	Exon 6 of 22	ENSP00000417826.1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128313 AN: 152060 Hom.: 56089 Cov.: 31

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

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.: 48 AF XY: 0.934 AC XY: 679003 AN XY: 726776

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

GnomAD4 genome AF: 0.844 AC: 128383 AN: 152178 Hom.: 56115 Cov.: 31 AF XY: 0.848 AC XY: 63085 AN XY: 74432

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
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)

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

Other links and lift over

dbSNP: rs3754090; hg19: chr1-224492746; COSMIC: COSV108020551; COSMIC: COSV108020551;