chr18-33957414-T-G

Position:

• chr18-33957414-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003787.5(NOL4):​c.1340A>C​(p.Gln447Pro) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: NOL4 NM_003787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

NOL4 (HGNC:7870): (nucleolar protein 4) Predicted to enable RNA binding activity. Predicted to be located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOL4	NM_003787.5	c.1340A>C	p.Gln447Pro	missense_variant	8/11	ENST00000261592.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOL4	ENST00000261592.10	c.1340A>C	p.Gln447Pro	missense_variant	8/11	1	NM_003787.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 18, 2024

The c.1340A>C (p.Q447P) alteration is located in exon 8 (coding exon 8) of the NOL4 gene. This alteration results from a A to C substitution at nucleotide position 1340, causing the glutamine (Q) at amino acid position 447 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.92
MutPred		0.15		Loss of helix (P = 0.028);.;.;
MVP		0.78
MPC		3.2
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.82

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: chr18-31537378;