14-103563009-T-C

Position:

• chr14-103563009-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370595.2(COA8):​c.8T>C​(p.Val3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,558,348 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (165 hom., cov: 35)
  • Exomes 𝑓: 0.0027 (171 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.295

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]

ENSG00000256500 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015886426).
• BP6: Variant 14-103563009-T-C is Benign according to our data. Variant chr14-103563009-T-C is described in ClinVar as [Benign]. Clinvar id is 381843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA8	NM_001370595.2	c.8T>C	p.Val3Ala	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	c.8T>C	p.Val3Ala	missense_variant	1/5	1	NM_001370595.2	ENSP00000386485.3
ENSG00000256500	ENST00000472726.3	c.8T>C	p.Val3Ala	missense_variant	1/18	2		ENSP00000439065.2

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3872 AN: 152178 Hom.: 165 Cov.: 35

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00534 AC: 896 AN: 167702 Hom.: 28 AF XY: 0.00384 AC XY: 354 AN XY: 92242

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.00534

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000316

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00271 AC: 3814 AN: 1406052 Hom.: 171 Cov.: 32 AF XY: 0.00235 AC XY: 1639 AN XY: 696108

Gnomad4 AFR exome AF: 0.0935

Gnomad4 AMR exome AF: 0.00578

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000270

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00602

GnomAD4 genome AF: 0.0255 AC: 3885 AN: 152296 Hom.: 165 Cov.: 35 AF XY: 0.0255 AC XY: 1896 AN XY: 74484

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.00185 Hom.: 8

Bravo AF: 0.0298

ESP6500AA AF: 0.0604 AC: 258

ESP6500EA AF: 0.000715 AC: 6

ExAC AF: 0.00419 AC: 483

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 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
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.1
DANN	Benign	0.50
DEOGEN2	Benign	0.0032	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00024	N
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N;.;.
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.96	N;N;N
REVEL	Benign	0.094
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.060
MVP		0.13
MPC		0.073
ClinPred		0.0026	T
GERP RS		2.2
Varity_R		0.019
gMVP		0.13

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: rs61733762; hg19: chr14-104029346;