16-67174237-T-C

Position:

• chr16-67174237-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000568146.1(NOL3):​c.68T>C​(p.Leu23Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOL3 ENST00000568146.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOL3	NM_001276309.3	c.68T>C	p.Leu23Pro	missense_variant	2/4	ENST00000564992.2	NP_001263238.1
NOL3	XM_047434851.1	c.254T>C	p.Leu85Pro	missense_variant	3/5		XP_047290807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOL3	ENST00000564992.2	c.68T>C	p.Leu23Pro	missense_variant	2/4	2	NM_001276309.3	ENSP00000457720	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 23 of the NOL3 protein (p.Leu23Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOL3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T;T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.096
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.76	T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	.;.;M;.;.;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D;.;.;D
Sift4G	Benign	0.11	T;D;T;T;T;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.77, 0.83, 0.66
MutPred		0.80		Loss of stability (P = 0.0181);Loss of stability (P = 0.0181);Loss of stability (P = 0.0181);Loss of stability (P = 0.0181);.;Loss of stability (P = 0.0181);
MVP		0.53
MPC		1.6
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.99

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: chr16-67208140;