6-99371503-T-C

Variant names:

• chr6-99371503-T-C
• rs6925344
• NM_017421.4:c.814A>G

Variant summary

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

The ENST00000254759.8(COQ3):​c.814A>G​(p.Ser272Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,604,922 control chromosomes in the GnomAD database, including 568,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S272N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (49955 hom., cov: 31)
  • Exomes 𝑓: 0.84 (518815 hom.)
• Consequence: COQ3 ENST00000254759.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 34 publications found

Genes affected

COQ3 (HGNC:18175): (coenzyme Q3, methyltransferase) Ubiquinone, also known as coenzyme Q, or Q, is a critical component of the electron transport pathways of both eukaryotes and prokaryotes (Jonassen and Clarke, 2000 [PubMed 10777520]). This lipid consists of a hydrophobic isoprenoid tail and a quinone head group. The tail varies in length depending on the organism, but its purpose is to anchor coenzyme Q to the membrane. The quinone head group is responsible for the activity of coenzyme Q in the respiratory chain. The S. cerevisiae COQ3 gene encodes an O-methyltransferase required for 2 steps in the biosynthetic pathway of coenzyme Q. This enzyme methylates an early coenzyme Q intermediate, 3,4-dihydroxy-5-polyprenylbenzoic acid, as well as the final intermediate in the pathway, converting demethyl-ubiquinone to coenzyme Q. The COQ3 gene product is also capable of methylating the distinct prokaryotic early intermediate 2-hydroxy-6-polyprenyl phenol.[supplied by OMIM, Mar 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.59554E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000254759.8. 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
	COQ3	NM_017421.4	MANE Select	c.814A>G	p.Ser272Gly	missense	Exon 6 of 7	NP_059117.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ3	ENST00000254759.8	TSL:1 MANE Select	c.814A>G	p.Ser272Gly	missense	Exon 6 of 7	ENSP00000254759.3
	COQ3	ENST00000369240.5	TSL:5	c.130A>G	p.Ser44Gly	missense	Exon 2 of 3	ENSP00000358243.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122828 AN: 151954 Hom.: 49914 Cov.: 31

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.924

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.820

GnomAD2 exomes AF: 0.851 AC: 209669 AN: 246488 AF XY: 0.854

Gnomad AFR exome AF: 0.710

Gnomad AMR exome AF: 0.923

Gnomad ASJ exome AF: 0.799

Gnomad EAS exome AF: 0.861

Gnomad FIN exome AF: 0.831

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.849

GnomAD4 exome AF: 0.844 AC: 1226718 AN: 1452850 Hom.: 518815 Cov.: 30 AF XY: 0.846 AC XY: 611844 AN XY: 723098

African (AFR) AF: 0.706 AC: 23326 AN: 33056

American (AMR) AF: 0.917 AC: 40174 AN: 43812

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20759 AN: 26022

East Asian (EAS) AF: 0.831 AC: 32678 AN: 39306

South Asian (SAS) AF: 0.919 AC: 78364 AN: 85228

European-Finnish (FIN) AF: 0.825 AC: 44025 AN: 53344

Middle Eastern (MID) AF: 0.844 AC: 4844 AN: 5742

European-Non Finnish (NFE) AF: 0.843 AC: 932243 AN: 1106268

Other (OTH) AF: 0.837 AC: 50305 AN: 60072

GnomAD4 genome AF: 0.808 AC: 122930 AN: 152072 Hom.: 49955 Cov.: 31 AF XY: 0.811 AC XY: 60273 AN XY: 74330

African (AFR) AF: 0.713 AC: 29569 AN: 41462

American (AMR) AF: 0.883 AC: 13494 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3468

East Asian (EAS) AF: 0.842 AC: 4356 AN: 5176

South Asian (SAS) AF: 0.924 AC: 4454 AN: 4820

European-Finnish (FIN) AF: 0.823 AC: 8682 AN: 10554

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.836 AC: 56866 AN: 68000

Other (OTH) AF: 0.822 AC: 1730 AN: 2104

Alfa AF: 0.825 Hom.: 184968

Bravo AF: 0.806

TwinsUK AF: 0.848 AC: 3143

ALSPAC AF: 0.852 AC: 3283

ESP6500AA AF: 0.714 AC: 3145

ESP6500EA AF: 0.836 AC: 7186

ExAC AF: 0.848 AC: 102933

Asia WGS AF: 0.890 AC: 3094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.39
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.038	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.1	N
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.053
ClinPred		0.0022	T
GERP RS		4.4
Varity_R		0.075
gMVP		0.43
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6925344; hg19: chr6-99819379; COSMIC: COSV54640126; COSMIC: COSV54640126;