chr9-128322889-C-T

Variant names:

• chr9-128322889-C-T
• rs1224494849
• NM_016035.5:c.31C>T

Variant summary

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

The NM_016035.5(COQ4):​c.31C>T​(p.Arg11Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,437,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0280
• Publications: 0 publications found

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]

TRUB2 (HGNC:17170): (TruB pseudouridine synthase family member 2) Pseudouridine is an abundant component of rRNAs and tRNAs and is enzymatically generated by isomerization of uridine by pseudouridine synthase (Zucchini et al., 2003 [PubMed 12736709]).[supplied by OMIM, Mar 2008]

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 (MetaRNN=0.12267992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016035.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ4	NM_016035.5	MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 1 of 7	NP_057119.3	Q9Y3A0-1
	COQ4	NM_001305942.2		c.31C>T	p.Arg11Trp	missense	Exon 1 of 4	NP_001292871.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ4	ENST00000300452.8	TSL:1 MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 1 of 7	ENSP00000300452.3	Q9Y3A0-1
	COQ4	ENST00000926106.1		c.31C>T	p.Arg11Trp	missense	Exon 1 of 8	ENSP00000596165.1
	COQ4	ENST00000926105.1		c.31C>T	p.Arg11Trp	missense	Exon 1 of 8	ENSP00000596164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1437368 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 714294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000304 AC: 1 AN: 32932

American (AMR) AF: 0.00 AC: 0 AN: 42146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 38782

South Asian (SAS) AF: 0.00 AC: 0 AN: 84676

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104124

Other (OTH) AF: 0.0000336 AC: 2 AN: 59520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.028
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.061
Sift	Benign	0.033	D
Sift4G	Uncertain	0.031	D
Polyphen		0.91	P
Vest4		0.20
MutPred		0.46		Loss of disorder (P = 0)
MVP		0.27
MPC		0.56
ClinPred		0.36	T
GERP RS		2.5
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.092
gMVP		0.45
Mutation Taster		=98/2	polymorphism

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: rs1224494849; hg19: chr9-131085168;