NM_004373.4:c.*190T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004373.4(COX6A1):​c.*190T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 504,762 control chromosomes in the GnomAD database, including 123,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41682 hom., cov: 33)
  • Exomes 𝑓: 0.68 (81473 hom.)
• Consequence: COX6A1 NM_004373.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-120440727-T-C is Benign according to our data. Variant chr12-120440727-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6A1	NM_004373.4	c.*190T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000229379.3	NP_004364.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6A1	ENST00000229379.3	c.*190T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_004373.4	ENSP00000229379.2
ENSG00000111780	ENST00000551806.1	c.174+2206T>C		intron_variant	Intron 2 of 4	3		ENSP00000450281.1
COX6A1	ENST00000549525.1	n.757T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110910 AN: 152030 Hom.: 41624 Cov.: 33

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.676 AC: 238528 AN: 352614 Hom.: 81473 Cov.: 4 AF XY: 0.676 AC XY: 124056 AN XY: 183494

African (AFR) AF: 0.909 AC: 9022 AN: 9920

American (AMR) AF: 0.596 AC: 7367 AN: 12360

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 7519 AN: 10888

East Asian (EAS) AF: 0.705 AC: 17870 AN: 25338

South Asian (SAS) AF: 0.683 AC: 17956 AN: 26298

European-Finnish (FIN) AF: 0.698 AC: 27003 AN: 38674

Middle Eastern (MID) AF: 0.650 AC: 1462 AN: 2250

European-Non Finnish (NFE) AF: 0.661 AC: 136398 AN: 206294

Other (OTH) AF: 0.677 AC: 13931 AN: 20592

GnomAD4 genome AF: 0.730 AC: 111026 AN: 152148 Hom.: 41682 Cov.: 33 AF XY: 0.729 AC XY: 54243 AN XY: 74366

African (AFR) AF: 0.914 AC: 37973 AN: 41550

American (AMR) AF: 0.613 AC: 9364 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2414 AN: 3472

East Asian (EAS) AF: 0.729 AC: 3772 AN: 5174

South Asian (SAS) AF: 0.675 AC: 3254 AN: 4820

European-Finnish (FIN) AF: 0.691 AC: 7301 AN: 10566

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44811 AN: 67992

Other (OTH) AF: 0.660 AC: 1389 AN: 2104

Alfa AF: 0.658 Hom.: 13207

Bravo AF: 0.729

Asia WGS AF: 0.707 AC: 2460 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.097
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: rs8903; hg19: chr12-120878530; COSMIC: COSV56663721; COSMIC: COSV56663721;