14-103562968-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_001370595.2(COA8):c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,358,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: COA8 NM_001370595.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.444

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090395).
• BP6: Variant 14-103562968-G-A is Benign according to our data. Variant chr14-103562968-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 742351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA8	NM_001370595.2	c.-34G>A		5_prime_UTR_variant	1/5	ENST00000409074.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8	c.-34G>A		5_prime_UTR_variant	1/5	1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1358054 Hom.: 0 Cov.: 32 AF XY: 0.00000299 AC XY: 2 AN XY: 669090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COA8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	16
Dann	Benign	0.90
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.018
Sift	Pathogenic	0.0	D
MutPred		0.18		Gain of phosphorylation at A2 (P = 0.0098);
MVP		0.030
ClinPred		0.15	T
GERP RS		-1.3

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: rs2076095937; hg19: chr14-104029305;