16-57447531-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020312.4(COQ9):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,308,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.680

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002901256).
• BP6: Variant 16-57447531-C-T is Benign according to our data. Variant chr16-57447531-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391794.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (35/152216) while in subpopulation SAS AF= 0.00582 (28/4812). AF 95% confidence interval is 0.00414. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ9	NM_020312.4	c.26C>T	p.Ala9Val	missense_variant	1/9	ENST00000262507.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ9	ENST00000262507.11	c.26C>T	p.Ala9Val	missense_variant	1/9	1	NM_020312.4	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152102 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000409 AC: 20 AN: 48904 Hom.: 0 AF XY: 0.000495 AC XY: 14 AN XY: 28272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00290

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000839

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 176 AN: 1156664 Hom.: 2 Cov.: 32 AF XY: 0.000204 AC XY: 114 AN XY: 558556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000745

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000363

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000115

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152216 Hom.: 0 Cov.: 34 AF XY: 0.000296 AC XY: 22 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.000365 AC: 41

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.1
Dann	Benign	0.77
DEOGEN2	Benign	0.00078	T;T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.59	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.020	N;N;N;N;N
REVEL	Benign	0.011
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.15
MutPred		0.21		Loss of disorder (P = 0.0712);Loss of disorder (P = 0.0712);Loss of disorder (P = 0.0712);Loss of disorder (P = 0.0712);Loss of disorder (P = 0.0712);
MVP		0.11
MPC		0.16
ClinPred		0.010	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.35

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: rs536567108; hg19: chr16-57481443;