15-74936505-T-C

Variant names:

• chr15-74936505-T-C
• rs4886642
• NM_004255.4:c.100+1410A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004255.4(COX5A):​c.100+1410A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,574 control chromosomes in the GnomAD database, including 4,968 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4968 hom., cov: 31)
• Consequence: COX5A NM_004255.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344
• Publications: 3 publications found

Genes affected

COX5A (HGNC:2267): (cytochrome c oxidase subunit 5A) Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Va of the human mitochondrial respiratory chain enzyme. A pseudogene COX5AP1 has been found in chromosome 14q22. [provided by RefSeq, Jul 2008]

COX5A Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex IV deficiency, nuclear type 20

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX5A	NM_004255.4	c.100+1410A>G		intron_variant	Intron 1 of 4	ENST00000322347.11	NP_004246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX5A	ENST00000322347.11	c.100+1410A>G		intron_variant	Intron 1 of 4	1	NM_004255.4	ENSP00000317780.6

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34804 AN: 151456 Hom.: 4976 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.243

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34808 AN: 151574 Hom.: 4968 Cov.: 31 AF XY: 0.238 AC XY: 17603 AN XY: 74044

African (AFR) AF: 0.290 AC: 11961 AN: 41268

American (AMR) AF: 0.208 AC: 3158 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3470

East Asian (EAS) AF: 0.652 AC: 3374 AN: 5172

South Asian (SAS) AF: 0.459 AC: 2210 AN: 4810

European-Finnish (FIN) AF: 0.216 AC: 2256 AN: 10444

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10316 AN: 67912

Other (OTH) AF: 0.243 AC: 511 AN: 2106

Alfa AF: 0.187 Hom.: 496

Bravo AF: 0.230

Asia WGS AF: 0.570 AC: 1979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	7.1
DANN	Benign	0.60
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs4886642; hg19: chr15-75228846;