chr1-226982107-C-A

Variant names:

• chr1-226982107-C-A
• NM_020247.5:c.811C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_020247.5(COQ8A):​c.811C>A​(p.Arg271Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COQ8A NM_020247.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24

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]

ENSG00000288674 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_020247.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226982107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 296015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5	c.811C>A	p.Arg271Ser	missense_variant	Exon 6 of 15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.811C>A	p.Arg271Ser	missense_variant	Exon 6 of 15	1	NM_020247.5	ENSP00000355739.3
ENSG00000288674	ENST00000366779.6	n.*5538C>A		non_coding_transcript_exon_variant	Exon 23 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6	n.*5538C>A		3_prime_UTR_variant	Exon 23 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457562 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724818

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.80	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.54		Loss of methylation at R271 (P = 0.0244);.;Loss of methylation at R271 (P = 0.0244);
MVP		0.95
MPC		0.26
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -4
DS_DL_spliceai		0.57		Position offset: 42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-227169808;