chr1-244835721-G-T

Position:

chr1-244835721-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_198076.6(COX20):c.7G>T(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,267,234 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 8 hom. )

Consequence

COX20
NM_198076.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.342

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Cytochrome c oxidase assembly protein COX20, mitochondrial (size 116) in uniprot entity COX20_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_198076.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0022479594).

BP6

Variant 1-244835721-G-T is Benign according to our data. Variant chr1-244835721-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 214269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00187 (285/152032) while in subpopulation AFR AF= 0.00632 (262/41462). AF 95% confidence interval is 0.00569. There are 1 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX20	NM_198076.6 linkuse as main transcript	c.7G>T	p.Ala3Ser	missense_variant	1/4	ENST00000411948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX20	ENST00000411948.7 linkuse as main transcript	c.7G>T	p.Ala3Ser	missense_variant	1/4	1	NM_198076.6	P1	Q5RI15-1
COX20	ENST00000391839.6 linkuse as main transcript	n.66G>T		non_coding_transcript_exon_variant	1/3	1
COX20	ENST00000366528.3 linkuse as main transcript	c.7G>T	p.Ala3Ser	missense_variant	1/5	2			Q5RI15-2
COX20	ENST00000498262.1 linkuse as main transcript	n.63G>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

285

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00631

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000392

AC:

AN:

15318

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

9586

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.000517

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000301

AC:

336

AN:

1115202

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

166

AN XY:

533528

show subpopulations

Gnomad4 AFR exome

AF:

0.00915

Gnomad4 AMR exome

AF:

0.000555

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000372

Gnomad4 SAS exome

AF:

0.0000671

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000545

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152032

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

135

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00632

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.00196

ExAC

AF:

0.000287

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex 4 deficiency, nuclear type 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.087

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.24

N;N

REVEL

Benign

0.025

Sift

Benign

0.037

D;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.028

B;.

Vest4

0.13

MVP

0.040

MPC

0.030

ClinPred

0.0095

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.17

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

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