6-99376065-C-T

Position:

• chr6-99376065-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_017421.4(COQ3):​c.604G>A​(p.Val202Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,162 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: COQ3 NM_017421.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011256456).
• BP6: Variant 6-99376065-C-T is Benign according to our data. Variant chr6-99376065-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 775079.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ3	NM_017421.4	c.604G>A	p.Val202Met	missense_variant	5/7	ENST00000254759.8	NP_059117.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ3	ENST00000254759.8	c.604G>A	p.Val202Met	missense_variant	5/7	1	NM_017421.4	ENSP00000254759.3
COQ3	ENST00000369240.5	c.45+1321G>A		intron_variant		5		ENSP00000358243.1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00267 AC: 671 AN: 251358 Hom.: 3 AF XY: 0.00266 AC XY: 362 AN XY: 135842

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00376 AC: 5490 AN: 1461814 Hom.: 16 Cov.: 32 AF XY: 0.00367 AC XY: 2669 AN XY: 727214

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00335

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00293 AC: 447 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74496

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00368 Hom.: 2

Bravo AF: 0.00288

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.030
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.16	B
Vest4		0.25
MVP		0.23
MPC		0.073
ClinPred		0.010	T
GERP RS		3.8
Varity_R		0.078
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs138873880; hg19: chr6-99823941;