16-67174368-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The ENST00000568146.1(NOL3):​c.199G>A​(p.Gly67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,422,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

NOL3
ENST00000568146.1 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.629
Variant links:
Genes affected
NOL3 (HGNC:7869): (nucleolar protein 3) This gene encodes an anti-apoptotic protein that has been shown to down-regulate the enzyme activities of caspase 2, caspase 8 and tumor protein p53. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.045868665).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOL3NM_001276309.3 linkuse as main transcriptc.199G>A p.Gly67Ser missense_variant 2/4 ENST00000564992.2 NP_001263238.1
NOL3XM_047434851.1 linkuse as main transcriptc.385G>A p.Gly129Ser missense_variant 3/5 XP_047290807.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOL3ENST00000564992.2 linkuse as main transcriptc.199G>A p.Gly67Ser missense_variant 2/42 NM_001276309.3 ENSP00000457720 P2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000110
AC:
2
AN:
181122
Hom.:
0
AF XY:
0.0000100
AC XY:
1
AN XY:
99544
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000748
Gnomad SAS exome
AF:
0.0000382
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000351
AC:
5
AN:
1422752
Hom.:
0
Cov.:
32
AF XY:
0.00000426
AC XY:
3
AN XY:
705050
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000241
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000510
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 28, 2023Variant summary: NOL3 c.199G>A (p.Gly67Ser) results in a non-conservative amino acid change located in the CARD domain (IPR001315) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 181122 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.199G>A in individuals affected with Myoclonus, Familial, 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
11
DANN
Benign
0.95
DEOGEN2
Benign
0.0018
T;T;T;.;.;.
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.065
N
LIST_S2
Benign
0.63
T;T;T;T;T;T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.046
T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-1.1
.;.;N;.;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
1.8
N;N;N;N;N;N
REVEL
Benign
0.052
Sift
Benign
1.0
T;T;T;.;.;T
Sift4G
Benign
0.78
T;T;T;T;T;T
Polyphen
0.0040
.;.;B;.;.;.
Vest4
0.19, 0.20, 0.19
MutPred
0.30
Loss of ubiquitination at K68 (P = 0.0877);Loss of ubiquitination at K68 (P = 0.0877);Loss of ubiquitination at K68 (P = 0.0877);Loss of ubiquitination at K68 (P = 0.0877);.;Loss of ubiquitination at K68 (P = 0.0877);
MVP
0.32
MPC
0.47
ClinPred
0.079
T
GERP RS
0.93
Varity_R
0.23

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs980077298; hg19: chr16-67208271; API