20-32453712-C-T

Variant names:

• chr20-32453712-C-T
• rs150489354
• NM_001256798.2:c.1169G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001256798.2(NOL4L):​c.1169G>A​(p.Ser390Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,558,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14544246).
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1169G>A	p.Ser390Asn	missense_variant	Exon 7 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.437G>A	p.Ser146Asn	missense_variant	Exon 4 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.437G>A	p.Ser146Asn	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.1169G>A	p.Ser390Asn	missense_variant	Exon 7 of 11	5	NM_001256798.2	ENSP00000483523.1
NOL4L	ENST00000359676.9	c.437G>A	p.Ser146Asn	missense_variant	Exon 4 of 8	2		ENSP00000352704.5
NOL4L	ENST00000475781.1	n.507G>A		non_coding_transcript_exon_variant	Exon 5 of 7	5		ENSP00000492149.1
ENSG00000236772	ENST00000442179.1	n.*105C>T		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000308 AC: 5 AN: 162400 AF XY: 0.00

Gnomad AFR exome AF: 0.000419

Gnomad AMR exome AF: 0.0000398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1406626 Hom.: 0 Cov.: 32 AF XY: 0.00000432 AC XY: 3 AN XY: 694618

African (AFR) AF: 0.000437 AC: 14 AN: 32024

American (AMR) AF: 0.0000277 AC: 1 AN: 36160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25262

East Asian (EAS) AF: 0.00 AC: 0 AN: 36282

South Asian (SAS) AF: 0.00 AC: 0 AN: 80104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49778

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082992

Other (OTH) AF: 0.00 AC: 0 AN: 58326

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74332

African (AFR) AF: 0.000338 AC: 14 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000918 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000266 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437G>A (p.S146N) alteration is located in exon 4 (coding exon 3) of the NOL4L gene. This alteration results from a G to A substitution at nucleotide position 437, causing the serine (S) at amino acid position 146 to be replaced by an asparagine (N). 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	0.35
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.89	T
PhyloP100		5.3
PROVEAN	Benign	-1.0	N;.;.
REVEL	Benign	0.21
Sift	Benign	0.21	T;.;.
Sift4G	Benign	0.50	T;T;T
Polyphen		0.88	P;.;.
Vest4		0.60
MVP		0.068
MPC		0.57
ClinPred		0.077	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.28
Mutation Taster		=84/16	polymorphism

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

dbSNP: rs150489354; hg19: chr20-31041515;