NM_004373.4:c.*190T>G

Variant names:

• chr12-120440727-T-G
• rs8903
• NM_004373.4:c.*190T>G

Variant summary

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

The NM_004373.4(COX6A1):​c.*190T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COX6A1 NM_004373.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• Publications: 13 publications found

Genes affected

COX6A1 (HGNC:2277): (cytochrome c oxidase subunit 6A1) Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in the electron transfer and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity. It has been reported that there may be several pseudogenes on chromosomes 1, 6, 7q21, 7q31-32 and 12. However, only one pseudogene (COX6A1P) on chromosome 1p31.1 has been documented. [provided by RefSeq, Jul 2008]

COX6A1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease recessive intermediate D

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000111780 (HGNC:):

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 (BayesDel_noAF=-0.29).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX6A1	NM_004373.4	MANE Select	c.*190T>G		3_prime_UTR	Exon 3 of 3	NP_004364.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX6A1	ENST00000229379.3	TSL:1 MANE Select	c.*190T>G		3_prime_UTR	Exon 3 of 3	ENSP00000229379.2
	ENSG00000111780	ENST00000551806.1	TSL:3	c.174+2206T>G		intron	N/A	ENSP00000450281.1
	COX6A1	ENST00000549525.1	TSL:6	n.757T>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000283 AC: 1 AN: 353564 Hom.: 0 Cov.: 4 AF XY: 0.00000544 AC XY: 1 AN XY: 183980

African (AFR) AF: 0.00 AC: 0 AN: 9926

American (AMR) AF: 0.00 AC: 0 AN: 12386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10920

East Asian (EAS) AF: 0.00 AC: 0 AN: 25404

South Asian (SAS) AF: 0.00 AC: 0 AN: 26370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2262

European-Non Finnish (NFE) AF: 0.00000483 AC: 1 AN: 206898

Other (OTH) AF: 0.00 AC: 0 AN: 20660

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152068 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74260

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 13207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.097

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: rs8903; hg19: chr12-120878530;