rs1191346663

Variant names:

• chr4-73069376-C-A
• rs1191346663
• NM_001297732.2:c.274G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-73069376-C-A
• chr4-73069376-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001297732.2(COX18):​c.274G>T​(p.Ala92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000321 in 1,559,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A92V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0998162).

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.274G>T	p.Ala92Ser	missense	Exon 1 of 6	NP_001284661.1	B7ZL88
	COX18	NM_001300729.1		c.384G>T	p.Trp128Cys	missense	Exon 1 of 5	NP_001287658.1	Q8N8Q8
	COX18	NM_173827.4		c.274G>T	p.Ala92Ser	missense	Exon 1 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.274G>T	p.Ala92Ser	missense	Exon 1 of 6	ENSP00000425261.3	B7ZL88
	COX18	ENST00000295890.8	TSL:1	c.274G>T	p.Ala92Ser	missense	Exon 1 of 6	ENSP00000295890.4	Q8N8Q8-1
	COX18	ENST00000421792.2	TSL:1	n.380G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1407414 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695390

African (AFR) AF: 0.0000932 AC: 3 AN: 32192

American (AMR) AF: 0.00 AC: 0 AN: 37114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 36638

South Asian (SAS) AF: 0.00 AC: 0 AN: 80110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4534

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084850

Other (OTH) AF: 0.00 AC: 0 AN: 58276

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

African (AFR) AF: 0.0000241 AC: 1 AN: 41476

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.055
Sift	Benign	0.30	T
Sift4G	Benign	0.19	T
Polyphen		0.062	B
Vest4		0.15
MutPred		0.36		Loss of glycosylation at S89 (P = 0.0355)
MVP		0.15
MPC		0.31
ClinPred		0.18	T
GERP RS		4.0
PromoterAI		-0.054	Neutral
Varity_R		0.23
gMVP		0.42
Mutation Taster		=93/7	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: rs1191346663; hg19: chr4-73935093;