rs746878533

Variant names:

• chr4-73058211-C-A
• rs746878533
• NM_001297732.2:c.908G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-73058211-C-A
• chr4-73058211-C-T

Variant summary

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

The NM_001297732.2(COX18):​c.908G>T​(p.Arg303Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R303H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• Publications: 2 publications found

Genes affected

COX18 (HGNC:26801): (cytochrome c oxidase assembly factor COX18) This gene encodes a cytochrome c oxidase assembly protein. The encoded protein is essential for integral membrane protein insertion into the mitochondrial inner membrane. It is also required for cytochrome c oxidase assembly and activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297732.2. 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
	COX18	NM_001297732.2	MANE Select	c.908G>T	p.Arg303Leu	missense	Exon 6 of 6	NP_001284661.1	B7ZL88
	COX18	NM_001300729.1		c.914G>T	p.Arg305Leu	missense	Exon 5 of 5	NP_001287658.1	Q8N8Q8
	COX18	NM_173827.4		c.905G>T	p.Arg302Leu	missense	Exon 6 of 6	NP_776188.1	Q8N8Q8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX18	ENST00000507544.3	TSL:1 MANE Select	c.908G>T	p.Arg303Leu	missense	Exon 6 of 6	ENSP00000425261.3	B7ZL88
	COX18	ENST00000295890.8	TSL:1	c.905G>T	p.Arg302Leu	missense	Exon 6 of 6	ENSP00000295890.4	Q8N8Q8-1
	COX18	ENST00000449739.6	TSL:1	n.*414G>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000394583.2	Q8N8Q8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251140 AF XY: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461612 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727142

⚠️ 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: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.40	T
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.94	P
Vest4		0.30
MutPred		0.78		Loss of disorder (P = 0.0988)
MVP		0.43
MPC		0.75
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.62
gMVP		0.79
Mutation Taster		=55/45	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: rs746878533; hg19: chr4-73923928;