16-57456601-G-T

Variant names:

• chr16-57456601-G-T
• rs761979107
• NM_020312.4:c.476G>T

Variant summary

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

The NM_020312.4(COQ9):​c.476G>T​(p.Arg159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R159H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.935
• Publications: 0 publications found

Genes affected

COQ9 (HGNC:25302): (coenzyme Q9) This locus represents a mitochondrial ubiquinone biosynthesis gene. The encoded protein is likely necessary for biosynthesis of coenzyme Q10, as mutations at this locus have been associated with autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency.[provided by RefSeq, Sep 2010]

COQ9 Gene-Disease associations (from GenCC):

• encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

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=0.09460613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ9	NM_020312.4	c.476G>T	p.Arg159Leu	missense_variant	Exon 4 of 9	ENST00000262507.11	NP_064708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ9	ENST00000262507.11	c.476G>T	p.Arg159Leu	missense_variant	Exon 4 of 9	1	NM_020312.4	ENSP00000262507.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.9
DANN	Benign	0.91
DEOGEN2	Benign	0.015	T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
LIST_S2	Benign	0.82	T;T;D;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	N;.;.;.
PhyloP100		0.94
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N;N;N;D
Sift	Benign	0.039	D;D;D;T
Sift4G	Uncertain	0.014	D;D;D;D
Vest4		0.36
ClinPred		0.15	T
GERP RS		-7.8
Varity_R		0.15
gMVP		0.33

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: rs761979107; hg19: chr16-57490513;