chr14-103563041-C-G

Position:

chr14-103563041-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001370595.2(COA8):c.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,541,778 control chromosomes in the GnomAD database, including 85,328 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 7317 hom., cov: 34)

Exomes 𝑓: 0.33 ( 78011 hom. )

Consequence

COA8
NM_001370595.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

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=0.0045024753).

BP6

Variant 14-103563041-C-G is Benign according to our data. Variant chr14-103563041-C-G is described in ClinVar as [Benign]. Clinvar id is 379942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA8	NM_001370595.2 link	c.40C>G	p.Pro14Ala	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>G	p.Pro14Ala	missense_variant	1/5	1	NM_001370595.2	ENSP00000386485.3		A0A6Q8JUI0
ENSG00000256500	ENST00000472726.3 link	c.40C>G	p.Pro14Ala	missense_variant	1/18	2		ENSP00000439065.2		E7EVH7

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46261

AN:

152070

Hom.:

7315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.354

Gnomad EAS

AF:

0.0794

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.258

AC:

37220

AN:

144426

Hom.:

5619

AF XY:

0.264

AC XY:

20884

AN XY:

79108

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.0625

Gnomad SAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.264

Gnomad NFE exome

AF:

0.336

Gnomad OTH exome

AF:

0.287

GnomAD4 exome

AF:

0.329

AC:

456649

AN:

1389590

Hom.:

78011

Cov.:

AF XY:

0.327

AC XY:

224491

AN XY:

686606

show subpopulations

Gnomad4 AFR exome

AF:

0.289

Gnomad4 AMR exome

AF:

0.177

Gnomad4 ASJ exome

AF:

0.343

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.288

Gnomad4 NFE exome

AF:

0.351

Gnomad4 OTH exome

AF:

0.314

GnomAD4 genome

AF:

0.304

AC:

46278

AN:

152188

Hom.:

7317

Cov.:

AF XY:

0.297

AC XY:

22089

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.287

Gnomad4 AMR

AF:

0.250

Gnomad4 ASJ

AF:

0.354

Gnomad4 EAS

AF:

0.0793

Gnomad4 SAS

AF:

0.224

Gnomad4 FIN

AF:

0.277

Gnomad4 NFE

AF:

0.351

Gnomad4 OTH

AF:

0.310

Alfa

AF:

0.248

Hom.:

895

Bravo

AF:

0.301

TwinsUK

AF:

0.356

AC:

1319

ALSPAC

AF:

0.360

AC:

1388

ESP6500AA

AF:

0.220

AC:

924

ESP6500EA

AF:

0.294

AC:

2427

ExAC

AF:

0.181

AC:

18859

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2015

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. -

Mitochondrial complex 4 deficiency, nuclear type 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.030

DANN

Benign

0.67

DEOGEN2

Benign

0.0042

T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.29

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.26

N;.;.

PROVEAN

Benign

-0.37

N;N;N

REVEL

Benign

0.028

Sift

Benign

0.78

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.073

MPC

0.061

ClinPred

0.00089

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.023

gMVP

0.20

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