rs875989827

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 204622.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-234374303-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA6	NM_001206641.3	c.286T>C	p.Trp96Arg	missense_variant	2/3	ENST00000366615.10
COA6	NM_001012985.2	c.196T>C	p.Trp66Arg	missense_variant	2/3
COA6	NM_001301733.1	c.58T>C	p.Trp20Arg	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA6	ENST00000366615.10	c.286T>C	p.Trp96Arg	missense_variant	2/3	1	NM_001206641.3
COA6	ENST00000366613.1	c.196T>C	p.Trp66Arg	missense_variant	2/3	1
COA6	ENST00000366612.1	c.58T>C	p.Trp20Arg	missense_variant	1/2	1		P1
COA6	ENST00000619305.1	c.58T>C	p.Trp20Arg	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D;D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-13	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;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

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

LitVar

Other links and lift over

dbSNP: rs875989827; hg19: chr1-234510049;