14-103562970-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001370595.2(COA8):c.-32C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,513,624 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: COA8 NM_001370595.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.575

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006197691).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00115 (175/152300) while in subpopulation AMR AF= 0.00359 (55/15308). AF 95% confidence interval is 0.00283. There are 2 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA8	NM_001370595.2	c.-32C>G		5_prime_UTR_variant	1/5	ENST00000409074.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8	c.-32C>G		5_prime_UTR_variant	1/5	1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152184 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000679 AC: 86 AN: 126730 Hom.: 0 AF XY: 0.000666 AC XY: 47 AN XY: 70558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000801

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000877

GnomAD4 exome AF: 0.000846 AC: 1151 AN: 1361324 Hom.: 1 Cov.: 32 AF XY: 0.000865 AC XY: 580 AN XY: 670906

Gnomad4 AFR exome AF: 0.0000679

Gnomad4 AMR exome AF: 0.000603

Gnomad4 ASJ exome AF: 0.0000434

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000442

Gnomad4 FIN exome AF: 0.0000600

Gnomad4 NFE exome AF: 0.000966

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152300 Hom.: 2 Cov.: 34 AF XY: 0.00138 AC XY: 103 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000718 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000760 AC: 6

ExAC AF: 0.000491 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3 of the APOPT1 protein (p.Pro3Arg). This variant is present in population databases (rs374070748, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with APOPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1526292). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.8C>G (p.P3R) alteration is located in exon 1 (coding exon 1) of the APOPT1 gene. This alteration results from a C to G substitution at nucleotide position 8, causing the proline (P) at amino acid position 3 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.43	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.068
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.93	P;.
Vest4		0.32
MVP		0.62
MPC		0.38
ClinPred		0.19	T
GERP RS		1.9
Varity_R		0.14
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374070748; hg19: chr14-104029307;