chr1-224287957-G-C

Variant names:

• chr1-224287957-G-C
• NM_002533.4:c.1612C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002533.4(NVL):​c.1612C>G​(p.Gln538Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NVL NM_002533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116140515).

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.1612C>G	p.Gln538Glu	missense	Exon 14 of 23	NP_002524.2
	NVL	NM_001243147.2		c.1339C>G	p.Gln447Glu	missense	Exon 13 of 22	NP_001230076.1	O15381-5
	NVL	NM_206840.3		c.1294C>G	p.Gln432Glu	missense	Exon 13 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.1612C>G	p.Gln538Glu	missense	Exon 14 of 23	ENSP00000281701.6	O15381-1
	NVL	ENST00000391875.6	TSL:1	c.1294C>G	p.Gln432Glu	missense	Exon 13 of 22	ENSP00000375747.2	O15381-2
	NVL	ENST00000933815.1		c.1477C>G	p.Gln493Glu	missense	Exon 13 of 22	ENSP00000603874.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726946

African (AFR) AF: 0.00 AC: 0 AN: 33458

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

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	0.075
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.77
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.55	N
PhyloP100		3.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.27		Gain of relative solvent accessibility (P = 0.09)
MVP		0.97
MPC		0.29
ClinPred		0.76	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.36
Mutation Taster		=94/6	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

hg19: chr1-224475659;