4-73058182-A-T

Position:

• chr4-73058182-A-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.937T>A​(p.Ser313Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 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)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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=0.1279166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX18	NM_001297732.2	c.937T>A	p.Ser313Thr	missense_variant	6/6	ENST00000507544.3	NP_001284661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX18	ENST00000507544.3	c.937T>A	p.Ser313Thr	missense_variant	6/6	1	NM_001297732.2	ENSP00000425261	A1
COX18	ENST00000295890.8	c.934T>A	p.Ser312Thr	missense_variant	6/6	1		ENSP00000295890	P4
COX18	ENST00000449739.6	c.*443T>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000394583
COX18	ENST00000510031.1	c.*554T>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	1		ENSP00000424978

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 20, 2024

The c.934T>A (p.S312T) alteration is located in exon 6 (coding exon 6) of the COX18 gene. This alteration results from a T to A substitution at nucleotide position 934, causing the serine (S) at amino acid position 312 to be replaced by a threonine (T). 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	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	0.019
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.073
Sift	Benign	0.20	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.059	B;B
Vest4		0.17
MutPred		0.27		.;Gain of glycosylation at T317 (P = 0.0072);
MVP		0.43
MPC		0.29
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.56

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: chr4-73923899;