4-73069385-A-C

Position:

• chr4-73069385-A-C

Variant summary

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

The NM_001297732.2(COX18):​c.265T>G​(p.Ser89Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,212 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: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.765

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=0.124920964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX18	NM_001297732.2	c.265T>G	p.Ser89Ala	missense_variant	1/6	ENST00000507544.3	NP_001284661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX18	ENST00000507544.3	c.265T>G	p.Ser89Ala	missense_variant	1/6	1	NM_001297732.2	ENSP00000425261	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410212 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 09, 2023

The c.265T>G (p.S89A) alteration is located in exon 1 (coding exon 1) of the COX18 gene. This alteration results from a T to G substitution at nucleotide position 265, causing the serine (S) at amino acid position 89 to be replaced by an alanine (A). 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	0.071
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.62
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.033
Sift	Benign	0.33	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0010	B;B
Vest4		0.097
MutPred		0.47		Loss of glycosylation at S89 (P = 0.0355);Loss of glycosylation at S89 (P = 0.0355);
MVP		0.088
MPC		0.25
ClinPred		0.13	T
GERP RS		1.0
Varity_R		0.12
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-73935102;