1-224294309-C-T

Variant names:

• chr1-224294309-C-T
• rs753321668
• NM_002533.4:c.1283G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002533.4(NVL):​c.1283G>A​(p.Arg428Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NVL NM_002533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1283G>A	p.Arg428Gln	missense	Exon 12 of 23	NP_002524.2
	NVL	NM_001243147.2		c.1010G>A	p.Arg337Gln	missense	Exon 11 of 22	NP_001230076.1	O15381-5
	NVL	NM_206840.3		c.965G>A	p.Arg322Gln	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.1283G>A	p.Arg428Gln	missense	Exon 12 of 23	ENSP00000281701.6	O15381-1
	NVL	ENST00000391875.6	TSL:1	c.965G>A	p.Arg322Gln	missense	Exon 11 of 22	ENSP00000375747.2	O15381-2
	NVL	ENST00000933815.1		c.1148G>A	p.Arg383Gln	missense	Exon 11 of 22	ENSP00000603874.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251472 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

African (AFR) AF: 0.0000724 AC: 3 AN: 41410

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D
Sift4G	Benign	0.070	T
Polyphen		0.38	B
Vest4		0.39
MVP		0.95
MPC		0.40
ClinPred		0.56	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.82
Mutation Taster		=86/14	polymorphism

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: rs753321668; hg19: chr1-224482011; COSMIC: COSV99895005; COSMIC: COSV99895005;