rs547254482

chr16-57452920-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_020312.4(COQ9):c.362T>C(p.Ile121Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,613,660 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (7 hom.)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.98

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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01327613).
• BP6: Variant 16-57452920-T-C is Benign according to our data. Variant chr16-57452920-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214245.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152270) while in subpopulation SAS AF= 0.0085 (41/4822). AF 95% confidence interval is 0.00644. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ9	NM_020312.4	c.362T>C	p.Ile121Thr	missense_variant	3/9	ENST00000262507.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ9	ENST00000262507.11	c.362T>C	p.Ile121Thr	missense_variant	3/9	1	NM_020312.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000995 AC: 250 AN: 251352 Hom.: 2 AF XY: 0.00120 AC XY: 163 AN XY: 135850

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00797

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000452 AC: 661 AN: 1461390 Hom.: 7 Cov.: 31 AF XY: 0.000642 AC XY: 467 AN XY: 727006

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00728

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000529 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00112 AC: 136

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 27391121) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 17, 2017	The p.Ile121Thr variant (rs547254482) has been previously identified as a homozygote in a patient with developmental delay, head nodding, and hypotonia (Al-Shamsi 2016). However, the patient described in Al-Shamsi (2016) also harbored - as a homozygote - a previously-established pathogenic variant in TRAPPC11, and normal coenzyme Q10 activity was detected in the patient’s muscle tissue. The p.Ile121Thr variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in South Asian populations of 0.81% (identified in248 out of 30,782 chromosomes including 2 homozygotes). Thus, based on the available information, this variant is likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.92
MVP		0.55
MPC		0.68
ClinPred		0.20	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs547254482; hg19: chr16-57486832; COSMIC: COSV52647115; COSMIC: COSV52647115;