1-224308172-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002533.4(NVL):c.434A>G(p.Glu145Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NVL NM_002533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18401268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NVL	NM_002533.4	c.434A>G	p.Glu145Gly	missense_variant	6/23	ENST00000281701.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NVL	ENST00000281701.11	c.434A>G	p.Glu145Gly	missense_variant	6/23	1	NM_002533.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.434A>G (p.E145G) alteration is located in exon 6 (coding exon 6) of the NVL gene. This alteration results from a A to G substitution at nucleotide position 434, causing the glutamic acid (E) at amino acid position 145 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;N;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;T;D;D
Sift4G	Benign	0.32	T;T;.;D
Polyphen		0.0060	.;B;.;.
Vest4		0.18
MutPred		0.30		.;Loss of stability (P = 0.0105);.;.;
MVP		0.99
MPC		0.31
ClinPred		0.50	T
GERP RS		3.2
Varity_R		0.051
gMVP		0.078

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-224495874;