2-202295712-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015934.5(NOP58):c.946G>A(p.Val316Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,607,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: NOP58 NM_015934.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

Genes affected

NOP58 (HGNC:29926): (NOP58 ribonucleoprotein) The protein encoded by this gene is a core component of box C/D small nucleolar ribonucleoproteins. Some box C/D small nucleolar RNAs (snoRNAs), such as U3, U8, and U14, are dependent upon the encoded protein for their synthesis. This protein is SUMOylated, which is necessary for high affinity binding to snoRNAs. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2686984).
• BS2: High AC in GnomAd at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOP58	NM_015934.5	c.946G>A	p.Val316Ile	missense_variant	10/15	ENST00000264279.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOP58	ENST00000264279.10	c.946G>A	p.Val316Ile	missense_variant	10/15	1	NM_015934.5	P1
NOP58	ENST00000433543.2	c.518-1667G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 61 AN: 246064 Hom.: 0 AF XY: 0.000173 AC XY: 23 AN XY: 133056

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000236 AC: 343 AN: 1455240 Hom.: 0 Cov.: 30 AF XY: 0.000247 AC XY: 179 AN XY: 723848

Gnomad4 AFR exome AF: 0.000393

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000826

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74368

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000312 Hom.: 2

Bravo AF: 0.000249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

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

May 16, 2022

The c.946G>A (p.V316I) alteration is located in exon 10 (coding exon 10) of the NOP58 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the valine (V) at amino acid position 316 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.22
Sift	Benign	0.47	T
Sift4G	Benign	0.56	T
Polyphen		0.45	B
Vest4		0.60
MVP		0.67
MPC		0.71
ClinPred		0.37	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.28

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: rs150533873; hg19: chr2-203160435; COSMIC: COSV99970747; COSMIC: COSV99970747;