9-128322859-A-C

Variant names:

• chr9-128322859-A-C
• rs751764908
• NM_016035.5:c.1A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_016035.5(COQ4):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COQ4 NM_016035.5 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 25 codons. Genomic position: 128323018. Lost 0.091 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>C	p.Met1?	initiator_codon	Exon 1 of 7	NP_057119.3	Q9Y3A0-1
	COQ4	NM_001305942.2		c.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 1 of 7	ENSP00000300452.3	Q9Y3A0-1
	COQ4	ENST00000926106.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000596165.1
	COQ4	ENST00000926105.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000596164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410022 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 698382

African (AFR) AF: 0.00 AC: 0 AN: 31970

American (AMR) AF: 0.00 AC: 0 AN: 37048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 37010

South Asian (SAS) AF: 0.00 AC: 0 AN: 82348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089708

Other (OTH) AF: 0.00 AC: 0 AN: 58364

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.74
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.1	T
PhyloP100		0.91
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.031	B
Vest4		0.70
MutPred		0.98		Loss of helix (P = 0.0196)
MVP		0.18
ClinPred		0.97	D
GERP RS		4.1
PromoterAI		0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.47
Mutation Taster		=49/151	disease causing

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: rs751764908; hg19: chr9-131085138;