rs875989827

Variant names:

• chr1-234374303-T-C
• rs875989827
• NM_001206641.3:c.286T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-234374303-T-C
• chr1-234374303-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001206641.3(COA6):​c.286T>C​(p.Trp96Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COA6 NM_001206641.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.20
• Publications: 12 publications found

Genes affected

COA6 (HGNC:18025): (cytochrome c oxidase assembly factor 6) This gene encodes a member of the cytochrome c oxidase subunit 6B family. The encoded protein associates with cytochrome c oxidase may act has an cytochrome c oxidase mitochondrial respiratory complex VI assembly factor. Mutations in this gene may be associated with fatal infantile cardiomyopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

COA6 Gene-Disease associations (from GenCC):

• cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4

  Inheritance: AR, Unknown Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 1-234374303-T-C is Pathogenic according to our data. Variant chr1-234374303-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 204622.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206641.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA6	NM_001206641.3	MANE Select	c.286T>C	p.Trp96Arg	missense	Exon 2 of 3	NP_001193570.2
	COA6	NM_001012985.2		c.196T>C	p.Trp66Arg	missense	Exon 2 of 3	NP_001013003.1
	COA6	NM_001301733.1		c.58T>C	p.Trp20Arg	missense	Exon 1 of 2	NP_001288662.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA6	ENST00000366615.10	TSL:1 MANE Select	c.286T>C	p.Trp96Arg	missense	Exon 2 of 3	ENSP00000355574.5
	COA6	ENST00000366613.1	TSL:1	c.196T>C	p.Trp66Arg	missense	Exon 2 of 3	ENSP00000355572.1
	COA6	ENST00000366612.1	TSL:1	c.58T>C	p.Trp20Arg	missense	Exon 1 of 2	ENSP00000355571.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.76		Gain of disorder (P = 0.0047)
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.83
Mutation Taster		=11/89	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: rs875989827; hg19: chr1-234510049;