14-103563041-C-A

Position:

chr14-103563041-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001370595.2(COA8):c.40C>A(p.Pro14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,543,774 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0031 ( 10 hom. )

Consequence

COA8
NM_001370595.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.36

Variant links:

Genes affected

COA8 (HGNC:20492): (cytochrome c oxidase assembly factor 8) This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

COA8 links:

ENSG00000256500 (HGNC:):

ENSG00000256500 links:

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

KLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047018826).

BP6

Variant 14-103563041-C-A is Benign according to our data. Variant chr14-103563041-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 381449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-103563041-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00178 (271/152220) while in subpopulation NFE AF= 0.00328 (223/67980). AF 95% confidence interval is 0.00293. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA8	NM_001370595.2 link	c.40C>A	p.Pro14Thr	missense_variant	1/5	ENST00000409074.8	NP_001357524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COA8	ENST00000409074.8 link	c.40C>A	p.Pro14Thr	missense_variant	1/5	1	NM_001370595.2	ENSP00000386485.3		A0A6Q8JUI0
ENSG00000256500	ENST00000472726.3 link	c.40C>A	p.Pro14Thr	missense_variant	1/18	2		ENSP00000439065.2		E7EVH7

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

271

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00328

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00193

AC:

279

AN:

144426

Hom.:

AF XY:

0.00198

AC XY:

157

AN XY:

79108

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000839

Gnomad SAS exome

AF:

0.000427

Gnomad FIN exome

AF:

0.000474

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00190

GnomAD4 exome

AF:

0.00307

AC:

4270

AN:

1391554

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2039

AN XY:

687708

show subpopulations

Gnomad4 AFR exome

AF:

0.000752

Gnomad4 AMR exome

AF:

0.00187

Gnomad4 ASJ exome

AF:

0.000119

Gnomad4 EAS exome

AF:

0.0000544

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.000686

Gnomad4 NFE exome

AF:

0.00369

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00178

AC:

271

AN:

152220

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00328

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00119

Hom.:

895

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00415

AC:

ExAC

AF:

0.00124

AC:

129

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COA8: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2017

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. -

COA8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.25

DANN

Benign

0.78

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.17

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

PROVEAN

Benign

2.0

REVEL

Benign

0.051

Sift

Uncertain

0.029

MVP

0.014

ClinPred

0.000059

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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