chr1-224275372-C-T

Position:

• chr1-224275372-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_002533.4(NVL):​c.2049G>A​(p.Val683Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.007 in 1,614,110 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (68 hom.)
• Consequence: NVL NM_002533.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.455

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-224275372-C-T is Benign according to our data. Variant chr1-224275372-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2639928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.455 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NVL	NM_002533.4	c.2049G>A	p.Val683Val	synonymous_variant	17/23	ENST00000281701.11	NP_002524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NVL	ENST00000281701.11	c.2049G>A	p.Val683Val	synonymous_variant	17/23	1	NM_002533.4	ENSP00000281701.6

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00872

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00465 AC: 1168 AN: 251450 Hom.: 2 AF XY: 0.00481 AC XY: 654 AN XY: 135900

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00601

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00721 AC: 10545 AN: 1461810 Hom.: 68 Cov.: 31 AF XY: 0.00703 AC XY: 5114 AN XY: 727206

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.00870

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00474 AC XY: 353 AN XY: 74460

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00872

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00672 Hom.: 2

Bravo AF: 0.00442

EpiCase AF: 0.00900

EpiControl AF: 0.00747

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

NVL: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.7
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs150509891; hg19: chr1-224463074; COSMIC: COSV99895452;