Genetic Variant NM_198076.6:c.8C>T (chr1-244835722-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_198076.6(COX20):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000473 in 1,268,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. A3S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

COX20
NM_198076.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Variant links:

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]

COX20 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Cytochrome c oxidase assembly protein COX20, mitochondrial (size 116) in uniprot entity COX20_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_198076.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11715335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX20	NM_198076.6 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 4	ENST00000411948.7	NP_932342.1	Q5RI15-1B3KM21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COX20	ENST00000411948.7 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 4	1	NM_198076.6	ENSP00000406327.2	Q5RI15-1
COX20	ENST00000391839.6 link	n.67C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
COX20	ENST00000366528.3 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 5	2		ENSP00000355486.3	Q5RI15-2
COX20	ENST00000498262.1 link	n.64C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000448

AC:

AN:

1116622

Hom.:

Cov.:

AF XY:

0.00000187

AC XY:

AN XY:

534510

show subpopulations

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:

0.0000333

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000320

Gnomad4 OTH exome

AF:

0.0000223

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11

Uncertain:1

Apr 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.53

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.019

D;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.29

B;.

Vest4

0.20

MutPred

0.31

Gain of catalytic residue at A3 (P = 0.059);Gain of catalytic residue at A3 (P = 0.059);

MVP

0.092

MPC

0.054

ClinPred

0.87

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over