rs587777787

Variant names:

• chr14-103574110-AAAG-A
• rs587777787
• NM_001370595.2:c.331_333delGAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001370595.2(COA8):​c.331_333delGAA​(p.Glu111del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000123 in 1,380,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: COA8 NM_001370595.2 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.58
• Publications: 3 publications found

Genes affected

COA8 (HGNC:20492): (cytochrome c oxidase assembly factor 8) This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ENSG00000256500 (HGNC:):

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001370595.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-103574110-AAAG-A is Pathogenic according to our data. Variant chr14-103574110-AAAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156424.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370595.2. 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
	COA8	NM_001370595.2	MANE Select	c.331_333delGAA	p.Glu111del	conservative_inframe_deletion	Exon 3 of 5	NP_001357524.1
	COA8	NM_001302653.2		c.331_333delGAA	p.Glu111del	conservative_inframe_deletion	Exon 3 of 6	NP_001289582.2
	COA8	NM_001302654.2		c.331_333delGAA	p.Glu111del	conservative_inframe_deletion	Exon 3 of 4	NP_001289583.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.331_333delGAA	p.Glu111del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000386485.3
	ENSG00000256500	ENST00000472726.3	TSL:2	c.331_333delGAA	p.Glu111del	conservative_inframe_deletion	Exon 3 of 18	ENSP00000439065.2
	COA8	ENST00000674165.1		c.370_372delGAA	p.Glu124del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000501341.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000961 AC: 2 AN: 208042 AF XY: 0.00000878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

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: 0.00

GnomAD4 exome AF: 0.0000123 AC: 17 AN: 1380912 Hom.: 0 AF XY: 0.0000131 AC XY: 9 AN XY: 687432

African (AFR) AF: 0.00 AC: 0 AN: 29834

American (AMR) AF: 0.000129 AC: 4 AN: 30970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23190

East Asian (EAS) AF: 0.00 AC: 0 AN: 38758

South Asian (SAS) AF: 0.00 AC: 0 AN: 76836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1073030

Other (OTH) AF: 0.00 AC: 0 AN: 56832

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587777787; hg19: chr14-104040447;