18-34104125-C-G

Variant names:

• chr18-34104125-C-G
• rs767174619
• NM_003787.5:c.561G>C

Variant summary

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

The NM_003787.5(NOL4):​c.561G>C​(p.Met187Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,611,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NOL4 NM_003787.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06352502).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

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.561G>C	p.Met187Ile	missense	Exon 4 of 11	NP_003778.2	O94818-1
	NOL4	NM_001384467.1		c.630G>C	p.Met210Ile	missense	Exon 5 of 12	NP_001371396.1
	NOL4	NM_001384468.1		c.630G>C	p.Met210Ile	missense	Exon 5 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.561G>C	p.Met187Ile	missense	Exon 4 of 11	ENSP00000261592.4	O94818-1
	NOL4	ENST00000589544.5	TSL:1	c.561G>C	p.Met187Ile	missense	Exon 4 of 9	ENSP00000465450.1	O94818-2
	NOL4	ENST00000538587.5	TSL:2	c.339G>C	p.Met113Ile	missense	Exon 4 of 11	ENSP00000443472.1	O94818-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000838 AC: 21 AN: 250742 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000609

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: 0.0000137 AC: 20 AN: 1459294 Hom.: 0 Cov.: 30 AF XY: 0.00000964 AC XY: 7 AN XY: 725958

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.000448 AC: 20 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110008

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.0000657 AC: 1 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67936

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.76	N
PhyloP100		3.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.14
Sift	Benign	0.66	T
Sift4G	Benign	0.35	T
Polyphen		0.14	B
Vest4		0.32
MutPred		0.27		Loss of disorder (P = 0.0353)
MVP		0.10
MPC		0.13
ClinPred		0.089	T
GERP RS		5.4
Varity_R		0.32
gMVP		0.50

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: rs767174619; hg19: chr18-31684089;