20-32453754-G-C

Variant names:

• chr20-32453754-G-C
• rs563159052
• NM_001256798.2:c.1127C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001256798.2(NOL4L):​c.1127C>G​(p.Pro376Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000618 in 1,552,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P376A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055582613).
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1127C>G	p.Pro376Arg	missense_variant	Exon 7 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.395C>G	p.Pro132Arg	missense_variant	Exon 4 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.395C>G	p.Pro132Arg	missense_variant	Exon 4 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL4L	ENST00000621426.7	c.1127C>G	p.Pro376Arg	missense_variant	Exon 7 of 11	5	NM_001256798.2	ENSP00000483523.1
NOL4L	ENST00000359676.9	c.395C>G	p.Pro132Arg	missense_variant	Exon 4 of 8	2		ENSP00000352704.5
NOL4L	ENST00000475781.1	n.465C>G		non_coding_transcript_exon_variant	Exon 5 of 7	5		ENSP00000492149.1
ENSG00000236772	ENST00000442179.1	n.*147G>C		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000838 AC: 13 AN: 155084 AF XY: 0.0000978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000863

Gnomad FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000550 AC: 77 AN: 1400684 Hom.: 1 Cov.: 32 AF XY: 0.0000593 AC XY: 41 AN XY: 690960

African (AFR) AF: 0.0000315 AC: 1 AN: 31778

American (AMR) AF: 0.00 AC: 0 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25190

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35964

South Asian (SAS) AF: 0.0000630 AC: 5 AN: 79348

European-Finnish (FIN) AF: 0.000122 AC: 6 AN: 49360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000574 AC: 62 AN: 1079528

Other (OTH) AF: 0.0000172 AC: 1 AN: 58070

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74418

African (AFR) AF: 0.0000482 AC: 2 AN: 41530

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000203 Hom.: 0

Bravo AF: 0.000155

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395C>G (p.P132R) alteration is located in exon 4 (coding exon 3) of the NOL4L gene. This alteration results from a C to G substitution at nucleotide position 395, causing the proline (P) at amino acid position 132 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Benign	0.63
DEOGEN2	Benign	0.044	T;T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.90	T
PhyloP100		4.2
PROVEAN	Benign	-0.36	N;.;.
REVEL	Benign	0.089
Sift	Benign	0.036	D;.;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.93	P;.;.
Vest4		0.49
MutPred		0.22		Loss of catalytic residue at P131 (P = 0.0168);.;Loss of catalytic residue at P131 (P = 0.0168);
MVP		0.043
MPC		0.42
ClinPred		0.11	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.16
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs563159052; hg19: chr20-31041557;