4-73065387-C-T

Position:

• chr4-73065387-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001297732.2(COX18):​c.461G>A​(p.Arg154Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16104338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX18	NM_001297732.2	c.461G>A	p.Arg154Lys	missense_variant	3/6	ENST00000507544.3	NP_001284661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX18	ENST00000507544.3	c.461G>A	p.Arg154Lys	missense_variant	3/6	1	NM_001297732.2	ENSP00000425261.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461066 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.461G>A (p.R154K) alteration is located in exon 3 (coding exon 3) of the COX18 gene. This alteration results from a G to A substitution at nucleotide position 461, causing the arginine (R) at amino acid position 154 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.65
DEOGEN2	Benign	0.095	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.93	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.25
Sift	Benign	0.72	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	B;B
Vest4		0.30
MutPred		0.52		Loss of MoRF binding (P = 0.0875);Loss of MoRF binding (P = 0.0875);
MVP		0.26
MPC		0.30
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1720396883; hg19: chr4-73931104;