4-73064835-G-C

Variant names:

• chr4-73064835-G-C
• rs3762883
• NM_001297732.2:c.666C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The ENST00000507544.3(COX18):​c.666C>G​(p.Pro222Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,644 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: COX18 ENST00000507544.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 17 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-0.082 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00117 (1704/1461542) while in subpopulation SAS AF = 0.0173 (1490/86246). AF 95% confidence interval is 0.0165. There are 41 homozygotes in GnomAdExome4. There are 1194 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000507544.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX18	NM_001297732.2	MANE Select	c.666C>G	p.Pro222Pro	synonymous	Exon 4 of 6	NP_001284661.1
	COX18	NM_001300729.1		c.672C>G	p.Pro224Pro	synonymous	Exon 3 of 5	NP_001287658.1
	COX18	NM_173827.4		c.663C>G	p.Pro221Pro	synonymous	Exon 4 of 6	NP_776188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX18	ENST00000507544.3	TSL:1 MANE Select	c.666C>G	p.Pro222Pro	synonymous	Exon 4 of 6	ENSP00000425261.3
	COX18	ENST00000295890.8	TSL:1	c.663C>G	p.Pro221Pro	synonymous	Exon 4 of 6	ENSP00000295890.4
	COX18	ENST00000449739.6	TSL:1	n.*172C>G		non_coding_transcript_exon	Exon 3 of 5	ENSP00000394583.2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 151984 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00228 AC: 574 AN: 251342 AF XY: 0.00292

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00117 AC: 1704 AN: 1461542 Hom.: 41 Cov.: 34 AF XY: 0.00164 AC XY: 1194 AN XY: 727072

African (AFR) AF: 0.00233 AC: 78 AN: 33464

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0173 AC: 1490 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111784

Other (OTH) AF: 0.00149 AC: 90 AN: 60378

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152102 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74350

African (AFR) AF: 0.00253 AC: 105 AN: 41486

American (AMR) AF: 0.000523 AC: 8 AN: 15292

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

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

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.0000319 Hom.: 18161

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.50
PhyloP100		-0.082
Mutation Taster		=100/0	polymorphism

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: rs3762883; hg19: chr4-73930552;