rs16846649

Variant names:

• chr1-224326270-T-C
• rs16846649
• NM_002533.4:c.131+121A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 -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 rank	MANE	Protein	UniProt
NVL	NM_002533.4	c.131+121A>G		intron_variant	Intron 2 of 22	ENST00000281701.11	NP_002524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NVL	ENST00000281701.11	c.131+121A>G		intron_variant	Intron 2 of 22	1	NM_002533.4	ENSP00000281701.6

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

African (AFR) AF: 0.0136 AC: 190 AN: 13948

American (AMR) AF: 0.0311 AC: 650 AN: 20886

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 870 AN: 14430

East Asian (EAS) AF: 0.0420 AC: 1409 AN: 33538

South Asian (SAS) AF: 0.117 AC: 5069 AN: 43234

European-Finnish (FIN) AF: 0.0801 AC: 3245 AN: 40514

Middle Eastern (MID) AF: 0.0603 AC: 178 AN: 2950

European-Non Finnish (NFE) AF: 0.0856 AC: 25758 AN: 300920

Other (OTH) AF: 0.0710 AC: 1952 AN: 27474

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

African (AFR) AF: 0.0138 AC: 574 AN: 41560

American (AMR) AF: 0.0395 AC: 604 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3470

East Asian (EAS) AF: 0.0495 AC: 257 AN: 5190

South Asian (SAS) AF: 0.107 AC: 516 AN: 4830

European-Finnish (FIN) AF: 0.0796 AC: 844 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0896 AC: 6093 AN: 68014

Other (OTH) AF: 0.0477 AC: 101 AN: 2116

Alfa AF: 0.0578 Hom.: 191

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
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs16846649; hg19: chr1-224513972; COSMIC: COSV99894584;