1-234373840-G-A

Position:

chr1-234373840-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001012985.2(COA6):c.122G>A(p.Ser41Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,613,214 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 7 hom. )

Consequence

COA6
NM_001012985.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.949

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-234373840-G-A is Benign according to our data. Variant chr1-234373840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 506397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000573 (837/1460896) while in subpopulation AFR AF= 0.0192 (642/33450). AF 95% confidence interval is 0.018. There are 7 homozygotes in gnomad4_exome. There are 375 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA6	NM_001206641.3 linkuse as main transcript	c.212+162G>A		intron_variant		ENST00000366615.10	NP_001193570.2	Q5JTJ3-2
COA6	NM_001012985.2 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/3		NP_001013003.1	Q5JTJ3-1
COA6	NM_001301733.1 linkuse as main transcript	c.-406G>A		5_prime_UTR_variant	1/2		NP_001288662.1	Q5JTJ3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COA6	ENST00000366613.1 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/3	1		ENSP00000355572.1	Q5JTJ3-1
COA6	ENST00000366612 linkuse as main transcript	c.-406G>A		5_prime_UTR_variant	1/2	1		ENSP00000355571.1	Q5JTJ3-3
COA6	ENST00000366615.10 linkuse as main transcript	c.212+162G>A		intron_variant		1	NM_001206641.3	ENSP00000355574.5	Q5JTJ3-2
COA6	ENST00000619305.1 linkuse as main transcript	c.-17+162G>A		intron_variant		1		ENSP00000479686.1	Q5JTJ3-3

Frequencies

GnomAD3 genomes

AF:

0.00449

AC:

683

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00127

AC:

318

AN:

251120

Hom.:

AF XY:

0.000936

AC XY:

127

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000573

AC:

837

AN:

1460896

Hom.:

Cov.:

AF XY:

0.000516

AC XY:

375

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.0192

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00459

AC:

699

AN:

152318

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

340

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0158

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00883

Hom.:

836

Bravo

AF:

0.00518

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00176

AC:

214

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.013

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.38

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.29

REVEL

Benign

0.081

Sift

Benign

0.092

Sift4G

Benign

0.096

Polyphen

0.18

Vest4

0.12

MVP

0.54

MPC

0.41

ClinPred

0.0080

GERP RS

0.95

Varity_R

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over