1-234373513-G-C

Position:

• chr1-234373513-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206641.3(COA6):​c.47G>C​(p.Ser16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,604,910 control chromosomes in the GnomAD database, including 218,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.60 (29116 hom., cov: 34)
  • Exomes 𝑓: 0.51 (189330 hom.)
• Consequence: COA6 NM_001206641.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.43

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.4871795E-7).
• BP6: Variant 1-234373513-G-C is Benign according to our data. Variant chr1-234373513-G-C is described in ClinVar as [Benign]. Clinvar id is 380009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA6	NM_001206641.3	c.47G>C	p.Ser16Thr	missense_variant	1/3	ENST00000366615.10	NP_001193570.2
COA6-AS1	NR_125961.1	n.81C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COA6	ENST00000366615.10	c.47G>C	p.Ser16Thr	missense_variant	1/3	1	NM_001206641.3	ENSP00000355574.5
COA6	ENST00000619305	c.-182G>C		5_prime_UTR_variant	1/3	1		ENSP00000479686.1
COA6-AS1	ENST00000451795.3	n.152C>G		non_coding_transcript_exon_variant	1/2	5
COA6-AS1	ENST00000685022.2	n.152C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90920 AN: 152106 Hom.: 29060 Cov.: 34

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.578

GnomAD3 exomes AF: 0.526 AC: 120956 AN: 229908 Hom.: 32928 AF XY: 0.513 AC XY: 65119 AN XY: 126918

Gnomad AFR exome AF: 0.848

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.496

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.498

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.506 AC: 735150 AN: 1452684 Hom.: 189330 Cov.: 61 AF XY: 0.503 AC XY: 362967 AN XY: 722014

Gnomad4 AFR exome AF: 0.855

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.565

Gnomad4 EAS exome AF: 0.427

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.432

Gnomad4 NFE exome AF: 0.499

Gnomad4 OTH exome AF: 0.527

GnomAD4 genome AF: 0.598 AC: 91023 AN: 152226 Hom.: 29116 Cov.: 34 AF XY: 0.592 AC XY: 44063 AN XY: 74416

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.549

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.572

Alfa AF: 0.533 Hom.: 7216

Bravo AF: 0.627

TwinsUK AF: 0.508 AC: 1884

ALSPAC AF: 0.492 AC: 1896

ExAC AF: 0.514 AC: 60149

Asia WGS AF: 0.483 AC: 1684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.20
DANN	Benign	0.82
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.041
Sift	Uncertain	0.020	D
Sift4G	Benign	0.11	T
Vest4		0.032
ClinPred		0.0077	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.019

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: rs10910420; hg19: chr1-234509259; COSMIC: COSV64016687; COSMIC: COSV64016687;