rs16846649

Positions:

• chr1-224326270-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002533.4(NVL):​c.131+121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 650,174 control chromosomes in the GnomAD database, including 2,155 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 0.061 (359 hom., cov: 32)
  • Exomes 𝑓: 0.079 (1796 hom.)
• Consequence: NVL NM_002533.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NVL	NM_002533.4	c.131+121A>G		intron_variant		ENST00000281701.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NVL	ENST00000281701.11	c.131+121A>G		intron_variant		1	NM_002533.4	P1

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9236 AN: 152162 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0796

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0790 AC: 39321 AN: 497894 Hom.: 1796 AF XY: 0.0813 AC XY: 21485 AN XY: 264216

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.0603

Gnomad4 EAS exome AF: 0.0420

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.0801

Gnomad4 NFE exome AF: 0.0856

Gnomad4 OTH exome AF: 0.0710

GnomAD4 genome AF: 0.0607 AC: 9237 AN: 152280 Hom.: 359 Cov.: 32 AF XY: 0.0618 AC XY: 4604 AN XY: 74466

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0796

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0725 Hom.: 145

Bravo AF: 0.0533

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.1
DANN	Benign	0.90

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: rs16846649; hg19: chr1-224513972; COSMIC: COSV99894584;