1-224308150-C-T

Variant names:

• chr1-224308150-C-T
• rs7534447
• NM_002533.4:c.456G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002533.4(NVL):​c.456G>A​(p.Arg152Arg) 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 1,613,864 control chromosomes in the GnomAD database, including 695,578 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 0.85 (56268 hom., cov: 31)
  • Exomes 𝑓: 0.93 (639310 hom.)
• Consequence: NVL NM_002533.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.611
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=0.611 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.456G>A	p.Arg152Arg	synonymous	Exon 6 of 23	NP_002524.2
	NVL	NM_206840.3		c.138G>A	p.Arg46Arg	synonymous	Exon 5 of 22	NP_996671.1
	NVL	NM_001243147.2		c.343-2984G>A		intron	N/A	NP_001230076.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	ENST00000281701.11	TSL:1 MANE Select	c.456G>A	p.Arg152Arg	synonymous	Exon 6 of 23	ENSP00000281701.6
	NVL	ENST00000391875.6	TSL:1	c.138G>A	p.Arg46Arg	synonymous	Exon 5 of 22	ENSP00000375747.2
	NVL	ENST00000492281.5	TSL:4	c.171G>A	p.Arg57Arg	synonymous	Exon 2 of 4	ENSP00000418380.1

Frequencies

GnomAD3 genomes AF: 0.845 AC: 128545 AN: 152046 Hom.: 56241 Cov.: 31

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.926

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: 231515 AN: 251368 AF XY: 0.927

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.933

Gnomad EAS exome AF: 0.900

Gnomad FIN exome AF: 0.972

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.934

GnomAD4 exome AF: 0.933 AC: 1364434 AN: 1461702 Hom.: 639310 Cov.: 57 AF XY: 0.934 AC XY: 679435 AN XY: 727146

African (AFR) AF: 0.586 AC: 19595 AN: 33466

American (AMR) AF: 0.955 AC: 42723 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 24367 AN: 26126

East Asian (EAS) AF: 0.917 AC: 36383 AN: 39676

South Asian (SAS) AF: 0.930 AC: 80183 AN: 86230

European-Finnish (FIN) AF: 0.973 AC: 51960 AN: 53420

Middle Eastern (MID) AF: 0.933 AC: 5380 AN: 5768

European-Non Finnish (NFE) AF: 0.943 AC: 1048422 AN: 1111914

Other (OTH) AF: 0.918 AC: 55421 AN: 60384

GnomAD4 genome AF: 0.845 AC: 128616 AN: 152162 Hom.: 56268 Cov.: 31 AF XY: 0.849 AC XY: 63202 AN XY: 74408

African (AFR) AF: 0.592 AC: 24536 AN: 41432

American (AMR) AF: 0.927 AC: 14155 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 3216 AN: 3472

East Asian (EAS) AF: 0.903 AC: 4672 AN: 5174

South Asian (SAS) AF: 0.922 AC: 4457 AN: 4832

European-Finnish (FIN) AF: 0.977 AC: 10381 AN: 10624

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.945 AC: 64262 AN: 68038

Other (OTH) AF: 0.868 AC: 1834 AN: 2114

Alfa AF: 0.908 Hom.: 189951

Bravo AF: 0.831

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	-0.80
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		0.61
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: rs7534447; hg19: chr1-224495852; COSMIC: COSV108020552; COSMIC: COSV108020552;