14-103563041-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 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.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8	c.40C>A	p.Pro14Thr	missense_variant	1/5	1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152102 Hom.: 0 Cov.: 34

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.: 1 AF XY: 0.00198 AC XY: 157 AN XY: 79108

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.: 10 Cov.: 38 AF XY: 0.00296 AC XY: 2039 AN XY: 687708

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.: 0 Cov.: 34 AF XY: 0.00161 AC XY: 120 AN XY: 74424

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: 12

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00124 AC: 129

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.17	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	2.0	N
REVEL	Benign	0.051
Sift	Uncertain	0.029	D
MVP		0.014
ClinPred		0.000059	T
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

Other links and lift over

dbSNP: rs2274268; hg19: chr14-104029378;