rs548317868

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_020247.5(COQ8A):​c.1049A>G​(p.Lys350Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,596,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K350E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

1
3
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.21

Publications

0 publications found
Variant links:
Genes affected
COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]
COQ8A Gene-Disease associations (from GenCC):
  • autosomal recessive ataxia due to ubiquinone deficiency
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
  • coenzyme Q10 deficiency
    Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_020247.5
BP4
Computational evidence support a benign effect (MetaRNN=0.021577686).
BP6
Variant 1-226983003-A-G is Benign according to our data. Variant chr1-226983003-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446786.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
COQ8A
NM_020247.5
MANE Select
c.1049A>Gp.Lys350Arg
missense
Exon 8 of 15NP_064632.2

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
COQ8A
ENST00000366777.4
TSL:1 MANE Select
c.1049A>Gp.Lys350Arg
missense
Exon 8 of 15ENSP00000355739.3
COQ8A
ENST00000366778.5
TSL:1
c.893A>Gp.Lys298Arg
missense
Exon 8 of 15ENSP00000355740.1
ENSG00000288674
ENST00000366779.6
TSL:2
n.*5776A>G
non_coding_transcript_exon
Exon 25 of 32ENSP00000355741.2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152218
Hom.:
0
Cov.:
34
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:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000349
AC:
76
AN:
217652
AF XY:
0.000498
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000366
GnomAD4 exome
AF:
0.000165
AC:
238
AN:
1444104
Hom.:
1
Cov.:
34
AF XY:
0.000251
AC XY:
180
AN XY:
717148
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33030
American (AMR)
AF:
0.00
AC:
0
AN:
42314
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25854
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38564
South Asian (SAS)
AF:
0.00272
AC:
229
AN:
84112
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50888
Middle Eastern (MID)
AF:
0.000377
AC:
2
AN:
5310
European-Non Finnish (NFE)
AF:
9.05e-7
AC:
1
AN:
1104366
Other (OTH)
AF:
0.000101
AC:
6
AN:
59666
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
18
36
54
72
90
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152336
Hom.:
0
Cov.:
34
AF XY:
0.000107
AC XY:
8
AN XY:
74488
show subpopulations
African (AFR)
AF:
0.0000240
AC:
1
AN:
41588
American (AMR)
AF:
0.00
AC:
0
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5154
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.000382
AC:
46
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Autosomal recessive ataxia due to ubiquinone deficiency (1)
-
-
1
not provided (1)
-
1
-
not specified (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T
Eigen
Benign
0.0049
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.022
T
MetaSVM
Benign
-1.0
T
PhyloP100
7.2
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.20
Sift
Benign
0.36
T
Sift4G
Benign
0.38
T
Polyphen
0.34
B
Vest4
0.68
MutPred
0.53
Gain of methylation at K350 (P = 0.0183)
MVP
0.52
MPC
0.047
ClinPred
0.081
T
GERP RS
5.7
Varity_R
0.26
gMVP
0.62
Mutation Taster
=60/40
polymorphism

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

Other links and lift over

dbSNP: rs548317868; hg19: chr1-227170704; API