chr20-32453455-A-T

Variant names:

• chr20-32453455-A-T
• NM_001256798.2:c.1346T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256798.2(NOL4L):​c.1346T>A​(p.Met449Lys) 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: 33)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

NOL4L (HGNC:16106): (nucleolar protein 4 like) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000236772 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1346T>A	p.Met449Lys	missense_variant	Exon 8 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.614T>A	p.Met205Lys	missense_variant	Exon 5 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.614T>A	p.Met205Lys	missense_variant	Exon 5 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL4L	ENST00000621426.7	c.1346T>A	p.Met449Lys	missense_variant	Exon 8 of 11	5	NM_001256798.2	ENSP00000483523.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.614T>A (p.M205K) alteration is located in exon 5 (coding exon 4) of the NOL4L gene. This alteration results from a T to A substitution at nucleotide position 614, causing the methionine (M) at amino acid position 205 to be replaced by a lysine (K). 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	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.051	D
PhyloP100		8.9
PROVEAN	Pathogenic	-4.8	D;.;.
REVEL	Pathogenic	0.76
Sift	Benign	0.039	D;.;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.90
MutPred		0.41		Loss of stability (P = 0.0038);.;Loss of stability (P = 0.0038);
MVP		0.43
MPC		3.5
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.80
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr20-31041258;