rs3754090

Positions:

• chr1-224305044-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong 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

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• 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/exons	MANE	Protein	UniProt
NVL	NM_002533.4	c.738G>A	p.Leu246Leu	synonymous_variant	7/23	ENST00000281701.11	NP_002524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NVL	ENST00000281701.11	c.738G>A	p.Leu246Leu	synonymous_variant	7/23	1	NM_002533.4	ENSP00000281701.6

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

GnomAD3 exomes AF: 0.921 AC: 230815 AN: 250744 Hom.: 107309 AF XY: 0.927 AC XY: 125609 AN XY: 135536

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 SAS exome AF: 0.932

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

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.955

Gnomad4 ASJ exome AF: 0.933

Gnomad4 EAS exome AF: 0.917

Gnomad4 SAS exome AF: 0.930

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.943

Gnomad4 OTH exome AF: 0.917

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

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.927

Gnomad4 ASJ AF: 0.927

Gnomad4 EAS AF: 0.903

Gnomad4 SAS AF: 0.923

Gnomad4 FIN AF: 0.977

Gnomad4 NFE AF: 0.944

Gnomad4 OTH AF: 0.868

Alfa AF: 0.922 Hom.: 83310

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
DANN	Benign	0.63
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs3754090; hg19: chr1-224492746;