dbSNP rs767665620: COQ4:p.Arg227Gly (chr9-128333526-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016035.5(COQ4):c.679C>G(p.Arg227Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R227H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COQ4
NM_016035.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

0 publications found

Variant links:

Genes affected

COQ4 (HGNC:19693): (coenzyme Q4) This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

COQ4 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

COQ4 links:

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ACMG classification

Classification was made for transcript

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 (MetaRNN=0.15727943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5 link	c.679C>G	p.Arg227Gly	missense_variant	Exon 7 of 7	ENST00000300452.8	NP_057119.3	Q9Y3A0-1
COQ4	NM_001305942.2 link	c.*55C>G		3_prime_UTR_variant	Exon 4 of 4		NP_001292871.2	A0A024R890

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8 link	c.679C>G	p.Arg227Gly	missense_variant	Exon 7 of 7	1	NM_016035.5	ENSP00000300452.3		Q9Y3A0-1
COQ4	ENST00000461102.1 link	n.2585C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32778

American (AMR)

AF:

0.00

AC:

AN:

42402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25638

East Asian (EAS)

AF:

0.00

AC:

AN:

38894

South Asian (SAS)

AF:

0.00

AC:

AN:

84108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106046

Other (OTH)

AF:

0.00

AC:

AN:

59688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.79

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.9

REVEL

Benign

0.065

Sift

Benign

0.41

Sift4G

Benign

0.34

Polyphen

0.0080

Vest4

0.25

MutPred

0.47

Loss of solvent accessibility (P = 0.0044);

MVP

0.50

MPC

0.53

ClinPred

0.27

GERP RS

4.9

Varity_R

0.22

gMVP

0.62

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over