rs387906299

Variant names:

• chr1-226986538-GCAC-G
• rs387906299
• NM_020247.5:c.1750_1752delACC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_020247.5(COQ8A):​c.1750_1752delACC​(p.Thr584del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,605,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T584T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: COQ8A NM_020247.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.32
• Publications: 13 publications found

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: G2P, Orphanet
• coenzyme Q10 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_020247.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-226986538-GCAC-G is Pathogenic according to our data. Variant chr1-226986538-GCAC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8A	NM_020247.5	MANE Select	c.1750_1752delACC	p.Thr584del	conservative_inframe_deletion	Exon 15 of 15	NP_064632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8A	ENST00000366777.4	TSL:1 MANE Select	c.1750_1752delACC	p.Thr584del	conservative_inframe_deletion	Exon 15 of 15	ENSP00000355739.3	Q8NI60-1
	COQ8A	ENST00000366778.5	TSL:1	c.1594_1596delACC	p.Thr532del	conservative_inframe_deletion	Exon 15 of 15	ENSP00000355740.1	Q8NI60-3
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*6477_*6479delACC		non_coding_transcript_exon	Exon 32 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0000974 AC: 14 AN: 143788 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000685

Gnomad ASJ AF: 0.00216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000772

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251330 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461732 Hom.: 0 AF XY: 0.0000798 AC XY: 58 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111970

Other (OTH) AF: 0.000149 AC: 9 AN: 60390

GnomAD4 genome AF: 0.0000974 AC: 14 AN: 143788 Hom.: 0 Cov.: 32 AF XY: 0.0000712 AC XY: 5 AN XY: 70226

African (AFR) AF: 0.0000258 AC: 1 AN: 38744

American (AMR) AF: 0.0000685 AC: 1 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.00216 AC: 7 AN: 3238

East Asian (EAS) AF: 0.00 AC: 0 AN: 4834

South Asian (SAS) AF: 0.00 AC: 0 AN: 4256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000772 AC: 5 AN: 64798

Other (OTH) AF: 0.00 AC: 0 AN: 1946

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Autosomal recessive ataxia due to ubiquinone deficiency (6)
3	-	-	not provided (3)
1	-	-	Possible mitochondrial disorder - nuclear genes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906299; hg19: chr1-227174239;