Genetic Variant NOL4L:p.Pro573Arg (chr20-32452340-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001256798.2(NOL4L):c.1718C>G(p.Pro573Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NOL4L
NM_001256798.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.85

Publications

0 publications found

Variant links:

Genes affected

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

NOL4L links:

ENSG00000236772 (HGNC:):

ENSG00000236772 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2 link	c.1718C>G	p.Pro573Arg	missense_variant	Exon 10 of 11	ENST00000621426.7	NP_001243727.1	Q96MY1Q6P0R2A0A087X0N3
NOL4L	NM_080616.6 link	c.986C>G	p.Pro329Arg	missense_variant	Exon 7 of 8		NP_542183.2	Q96MY1-1
NOL4L	NM_001351680.2 link	c.986C>G	p.Pro329Arg	missense_variant	Exon 7 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOL4L	ENST00000621426.7 link	c.1718C>G	p.Pro573Arg	missense_variant	Exon 10 of 11	5	NM_001256798.2	ENSP00000483523.1	A0A087X0N3
ENSG00000236772	ENST00000442179.1 link	n.716+627G>C		intron_variant	Intron 3 of 3	1
NOL4L	ENST00000359676.9 link	c.986C>G	p.Pro329Arg	missense_variant	Exon 7 of 8	2		ENSP00000352704.5	Q96MY1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248744

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.0000225

AC:

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

85878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110688

Other (OTH)

AF:

0.00

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.986C>G (p.P329R) alteration is located in exon 7 (coding exon 6) of the NOL4L gene. This alteration results from a C to G substitution at nucleotide position 986, causing the proline (P) at amino acid position 329 to be replaced by an arginine (R). 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

0.28

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0081

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.82

PhyloP100

6.8

PROVEAN

Uncertain

-3.2

D;.;.

REVEL

Benign

0.11

Sift

Benign

0.032

D;.;.

Sift4G

Benign

0.15

T;T;T

Polyphen

0.64

P;.;.

Vest4

0.79

MVP

0.082

MPC

0.83

ClinPred

0.90

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.37

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over