chr1-244842061-G-C

Position:

chr1-244842061-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_198076.6(COX20):c.157+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,587,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 0 hom. )

Consequence

COX20
NM_198076.6 splice_region, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:3

Conservation

PhyloP100: 1.62

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:

COX20 (HGNC:):

COX20 links:

HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

HNRNPU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-244842061-G-C is Pathogenic according to our data. Variant chr1-244842061-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 380082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX20	NM_198076.6 linkuse as main transcript	c.157+3G>C		splice_region_variant, intron_variant		ENST00000411948.7	NP_932342.1	Q5RI15-1B3KM21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX20	ENST00000411948.7 linkuse as main transcript	c.157+3G>C		splice_region_variant, intron_variant		1	NM_198076.6	ENSP00000406327.2		Q5RI15-1

Frequencies

GnomAD3 genomes

AF:

0.000632

AC:

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000571

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000568

AC:

142

AN:

249980

Hom.:

AF XY:

0.000606

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000902

AC:

1295

AN:

1435446

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

611

AN XY:

715794

show subpopulations

Gnomad4 AFR exome

AF:

0.0000916

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000722

GnomAD4 genome

AF:

0.000632

AC:

AN:

151860

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000571

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000563

EpiCase

AF:

0.000928

EpiControl

AF:

0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 11 (MIM#619054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant is predicted to result in an out-of- frame loss of exon 2. RT-PCR experiments using patient cells demonstrates an increased expression of the exon 2 deletion transcript and loss of the full length WT transcript compared with control cells (PMID: 30656193). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (1391 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple affected compound heterozygous individuals (ClinVar, PMIDs: 30656193). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2023	Variant summary: COX20 c.157+3G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. This impact on normal splicing was confirmed experimentally using fibroblasts from a compound heterozygous patient: only mRNA transcripts missing exon 2 could be detected, and full length COX20 mRNA transcripts were completely absent (Otero_2019). Furthermore, no protein products could be detected from these same patient fibroblasts, indicating a complete loss of protein product (Otero_2019). The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). c.157+3G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Mitochondrial Complex 4 Deficiency, Nuclear Type 11 (e.g. Otero_2019, Chakravorty_2020, Naess_2021). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 32999401, 32827528, 30656193). Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, four as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Dec 18, 2020	- -

not provided

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367956888, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with clinical features of mitochondrial complex IV deficiency (PMID: 30656193, 32827528, 32999401). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 380082). Studies have shown that this variant alters COX20 gene expression (PMID: 30656193). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2024	Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (PMID: 30656193); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32999401, 32606554, 32827528, 30656193, 37095481) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2023	PP1_strong, PP3, PM3_very_strong, PS3 -

Mitochondrial complex IV deficiency, nuclear type 1

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.81

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.81

Position offset: -3

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