chr16-57447516-C-T

Variant names:

• chr16-57447516-C-T
• rs2030148340
• NM_020312.4:c.11C>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.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000917 in 1,308,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.41
• 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]

CIAPIN1 (HGNC:28050): (cytokine induced apoptosis inhibitor 1) CIAPIN1 is a cytokine-induced inhibitor of apoptosis with no relation to apoptosis regulatory molecules of the BCL2 (MIM 151430) or CASP (see MIM 147678) families. Expression of CIAPIN1 is dependent on growth factor stimulation (Shibayama et al., 2004 [PubMed 14970183]).[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=0.10527077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020312.4. 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
	COQ9	NM_020312.4	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 9	NP_064708.1	O75208-1
	CIAPIN1	NM_020313.4	MANE Select	c.-230G>A		upstream_gene	N/A	NP_064709.2	Q6FI81-1
	CIAPIN1	NM_001308347.2		c.-230G>A		upstream_gene	N/A	NP_001295276.1	Q6FI81-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ9	ENST00000262507.11	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 9	ENSP00000262507.5	O75208-1
	COQ9	ENST00000895095.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 10	ENSP00000565154.1
	COQ9	ENST00000895096.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 9	ENSP00000565155.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000951 AC: 11 AN: 1156392 Hom.: 0 Cov.: 32 AF XY: 0.00000717 AC XY: 4 AN XY: 557674

African (AFR) AF: 0.00 AC: 0 AN: 23874

American (AMR) AF: 0.00 AC: 0 AN: 13532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16334

East Asian (EAS) AF: 0.00 AC: 0 AN: 27408

South Asian (SAS) AF: 0.00 AC: 0 AN: 35428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4190

European-Non Finnish (NFE) AF: 0.0000115 AC: 11 AN: 954388

Other (OTH) AF: 0.00 AC: 0 AN: 46164

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74348

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

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.083
Sift	Benign	0.069	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.29		Loss of disorder (P = 0.0762)
MVP		0.092
MPC		0.16
ClinPred		0.22	T
GERP RS		-0.47
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.074
gMVP		0.59
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: rs2030148340; hg19: chr16-57481428;