14-103562970-C-T

Variant names:

• chr14-103562970-C-T
• rs374070748
• NM_001370595.2:c.-32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370595.2(COA8):​c.-32C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,361,326 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: COA8 NM_001370595.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.575
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11198977).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370595.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA8	NM_001370595.2	MANE Select	c.-32C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001370595.2	MANE Select	c.-32C>T		5_prime_UTR	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.-32C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001289582.2	G3V4L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.-32C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.-32C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.-32C>T		5_prime_UTR	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1361326 Hom.: 0 Cov.: 32 AF XY: 0.00000745 AC XY: 5 AN XY: 670906

African (AFR) AF: 0.0000339 AC: 1 AN: 29466

American (AMR) AF: 0.00 AC: 0 AN: 33190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23062

East Asian (EAS) AF: 0.00 AC: 0 AN: 35802

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4588

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1068548

Other (OTH) AF: 0.0000177 AC: 1 AN: 56404

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.0053	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.57
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.059	B
Vest4		0.23
MutPred		0.29		Gain of catalytic residue at C4 (P = 0)
MVP		0.31
MPC		0.35
ClinPred		0.59	D
GERP RS		1.9
PromoterAI		-0.059	Neutral
Varity_R		0.13
gMVP		0.26
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs374070748; hg19: chr14-104029307;