18-33958363-C-A

Variant names:

• chr18-33958363-C-A
• rs777765707
• NM_003787.5:c.1112G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003787.5(NOL4):​c.1112G>T​(p.Arg371Leu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOL4 NM_003787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 5 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09839502).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOL4	NM_003787.5	MANE Select	c.1112G>T	p.Arg371Leu	missense	Exon 7 of 11	NP_003778.2	O94818-1
	NOL4	NM_001384467.1		c.1181G>T	p.Arg394Leu	missense	Exon 8 of 12	NP_001371396.1
	NOL4	NM_001384468.1		c.1181G>T	p.Arg394Leu	missense	Exon 8 of 11	NP_001371397.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOL4	ENST00000261592.10	TSL:1 MANE Select	c.1112G>T	p.Arg371Leu	missense	Exon 7 of 11	ENSP00000261592.4	O94818-1
	NOL4	ENST00000589544.5	TSL:1	c.1112G>T	p.Arg371Leu	missense	Exon 7 of 9	ENSP00000465450.1	O94818-2
	NOL4	ENST00000538587.5	TSL:2	c.890G>T	p.Arg297Leu	missense	Exon 7 of 11	ENSP00000443472.1	O94818-3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 17 AN: 136432 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000994

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000490

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246480 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000191 AC: 268 AN: 1405420 Hom.: 0 Cov.: 31 AF XY: 0.000203 AC XY: 142 AN XY: 698010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32040

American (AMR) AF: 0.000720 AC: 30 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24678

East Asian (EAS) AF: 0.0000533 AC: 2 AN: 37552

South Asian (SAS) AF: 0.00102 AC: 77 AN: 75778

European-Finnish (FIN) AF: 0.000118 AC: 6 AN: 50868

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5518

European-Non Finnish (NFE) AF: 0.000121 AC: 131 AN: 1079854

Other (OTH) AF: 0.000348 AC: 20 AN: 57444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000124 AC: 17 AN: 136558 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 10 AN XY: 67280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000190 AC: 7 AN: 36766

American (AMR) AF: 0.00 AC: 0 AN: 13672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3158

East Asian (EAS) AF: 0.00133 AC: 6 AN: 4500

South Asian (SAS) AF: 0.00 AC: 0 AN: 4252

European-Finnish (FIN) AF: 0.0000994 AC: 1 AN: 10064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.0000490 AC: 3 AN: 61238

Other (OTH) AF: 0.00 AC: 0 AN: 1834

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000102 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.65
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.43	B
Vest4		0.46
MutPred		0.29		Loss of solvent accessibility (P = 0.0217)
MVP		0.41
MPC		0.22
ClinPred		0.12	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs777765707; hg19: chr18-31538327;