chr1-244835716-T-C

Position:

• chr1-244835716-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_198076.6(COX20):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,245,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: COX20 NM_198076.6 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.81

Genes affected

COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX20	NM_198076.6	c.2T>C	p.Met1?	start_lost	1/4	ENST00000411948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX20	ENST00000411948.7	c.2T>C	p.Met1?	start_lost	1/4	1	NM_198076.6	P1
COX20	ENST00000391839.6	n.61T>C		non_coding_transcript_exon_variant	1/3	1
COX20	ENST00000366528.3	c.2T>C	p.Met1?	start_lost	1/5	2
COX20	ENST00000498262.1	n.58T>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149434 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

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: 0.0000228 AC: 25 AN: 1095732 Hom.: 0 Cov.: 31 AF XY: 0.0000267 AC XY: 14 AN XY: 524324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000787

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000248

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149434 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 72884

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jul 30, 2024

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.002%). Start lost - reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alternate start codon. in silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.99 (damaging >=0.6)]. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1320208). This variant has not been reported in the literature in individuals affected with COX20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the COX20 mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ROM1 cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.067	B;.
Vest4		0.88
MutPred		0.99		Gain of glycosylation at M1 (P = 2e-04);Gain of glycosylation at M1 (P = 2e-04);
MVP		0.24
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs771264340; hg19: chr1-244999018;