1-234374226-A-G

Position:

• chr1-234374226-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001206641.3(COA6):​c.213-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 1,605,424 control chromosomes in the GnomAD database, including 3,603 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1557 hom., cov: 31)
  • Exomes 𝑓: 0.025 (2046 hom.)
• Consequence: COA6 NM_001206641.3 splice_region, intron
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.434

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 1-234374226-A-G is Benign according to our data. Variant chr1-234374226-A-G is described in ClinVar as [Benign]. Clinvar id is 380182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA6	NM_001206641.3	c.213-4A>G		splice_region_variant, intron_variant		ENST00000366615.10	NP_001193570.2
COA6	NM_001301733.1	c.-20A>G		5_prime_UTR_variant	1/2		NP_001288662.1
COA6	NM_001012985.2	c.123-4A>G		splice_region_variant, intron_variant			NP_001013003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COA6	ENST00000366612	c.-20A>G		5_prime_UTR_variant	1/2	1		ENSP00000355571.1
COA6	ENST00000366615.10	c.213-4A>G		splice_region_variant, intron_variant		1	NM_001206641.3	ENSP00000355574.5
COA6	ENST00000366613.1	c.123-4A>G		splice_region_variant, intron_variant		1		ENSP00000355572.1
COA6	ENST00000619305.1	c.-16-4A>G		splice_region_variant, intron_variant		1		ENSP00000479686.1

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14294 AN: 151732 Hom.: 1556 Cov.: 31

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0963

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.00648

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0805

GnomAD3 exomes AF: 0.0537 AC: 13167 AN: 245322 Hom.: 1034 AF XY: 0.0458 AC XY: 6101 AN XY: 133092

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.0984

Gnomad SAS exome AF: 0.0398

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0253 AC: 36806 AN: 1453580 Hom.: 2046 Cov.: 32 AF XY: 0.0247 AC XY: 17852 AN XY: 723336

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.0429

Gnomad4 FIN exome AF: 0.00768

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0943 AC: 14312 AN: 151844 Hom.: 1557 Cov.: 31 AF XY: 0.0925 AC XY: 6865 AN XY: 74194

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0835

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.00648

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0811

Alfa AF: 0.0348 Hom.: 267

Bravo AF: 0.112

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
not provided, no classification provided	in vitro	Seelig Lab, University of Washington	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	21
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: 1
DS_AL_spliceai		0.23		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73099933; hg19: chr1-234509972;