1-224294382-C-T

Variant names:

• chr1-224294382-C-T
• rs34631151
• NM_002533.4:c.1210G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002533.4(NVL):​c.1210G>A​(p.Val404Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0383 in 1,613,936 control chromosomes in the GnomAD database, including 1,423 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 0.029 (88 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1335 hom.)
• Consequence: NVL NM_002533.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07
• Publications: 13 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 (MetaRNN=0.009979695).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (4471/152180) while in subpopulation NFE AF = 0.0402 (2732/68020). AF 95% confidence interval is 0.0389. There are 88 homozygotes in GnomAd4. There are 2216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 88 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	NM_002533.4	MANE Select	c.1210G>A	p.Val404Ile	missense	Exon 12 of 23	NP_002524.2
	NVL	NM_001243147.2		c.937G>A	p.Val313Ile	missense	Exon 11 of 22	NP_001230076.1	O15381-5
	NVL	NM_206840.3		c.892G>A	p.Val298Ile	missense	Exon 11 of 22	NP_996671.1	O15381-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	ENST00000281701.11	TSL:1 MANE Select	c.1210G>A	p.Val404Ile	missense	Exon 12 of 23	ENSP00000281701.6	O15381-1
	NVL	ENST00000391875.6	TSL:1	c.892G>A	p.Val298Ile	missense	Exon 11 of 22	ENSP00000375747.2	O15381-2
	NVL	ENST00000933815.1		c.1075G>A	p.Val359Ile	missense	Exon 11 of 22	ENSP00000603874.1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4472 AN: 152062 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0338 AC: 8489 AN: 251402 AF XY: 0.0353

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0393 AC: 57399 AN: 1461756 Hom.: 1335 Cov.: 31 AF XY: 0.0393 AC XY: 28575 AN XY: 727188

African (AFR) AF: 0.00571 AC: 191 AN: 33478

American (AMR) AF: 0.0218 AC: 977 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 2327 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0260 AC: 2244 AN: 86256

European-Finnish (FIN) AF: 0.0354 AC: 1891 AN: 53400

Middle Eastern (MID) AF: 0.0472 AC: 272 AN: 5766

European-Non Finnish (NFE) AF: 0.0424 AC: 47117 AN: 1111908

Other (OTH) AF: 0.0394 AC: 2378 AN: 60396

GnomAD4 genome AF: 0.0294 AC: 4471 AN: 152180 Hom.: 88 Cov.: 32 AF XY: 0.0298 AC XY: 2216 AN XY: 74392

African (AFR) AF: 0.00754 AC: 313 AN: 41530

American (AMR) AF: 0.0291 AC: 444 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 313 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0256 AC: 123 AN: 4812

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10592

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2732 AN: 68020

Other (OTH) AF: 0.0323 AC: 68 AN: 2108

Alfa AF: 0.0373 Hom.: 429

Bravo AF: 0.0271

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0448 AC: 385

ExAC AF: 0.0333 AC: 4048

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0423

EpiControl AF: 0.0455

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.058	T
Polyphen		0.99	D
Vest4		0.27
MPC		0.68
ClinPred		0.018	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.58
Mutation Taster		=97/3	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: rs34631151; hg19: chr1-224482084; COSMIC: COSV108748234; COSMIC: COSV108748234;