dbSNP rs751764908: COQ4:p.Met1? (chr9-128322859-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.908

Publications

0 publications found

Variant links:

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]

COQ4 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

COQ4 links:

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ACMG classification

Classification was made for transcript

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 7	ENST00000300452.8	NP_057119.3	Q9Y3A0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COQ4	ENST00000300452.8 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 7	1	NM_016035.5	ENSP00000300452.3	Q9Y3A0-1
COQ4	ENST00000372875.3 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 4	2		ENSP00000361966.3	Q5T4B9
COQ4	ENST00000608951.5 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 3	2		ENSP00000476323.1	V9GY32
COQ4	ENST00000609948.1 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 2	2		ENSP00000477292.1	V9GZ09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410022

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31970

American (AMR)

AF:

0.00

AC:

AN:

37048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

37010

South Asian (SAS)

AF:

0.00

AC:

AN:

82348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1089708

Other (OTH)

AF:

0.00

AC:

AN:

58364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0034

T;T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Benign

-1.1

PhyloP100

0.91

PROVEAN

Benign

-0.40

N;.;.;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.031

B;.;.;B

Vest4

0.70

MutPred

0.98

Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);

MVP

0.18

ClinPred

0.97

GERP RS

4.1

PromoterAI

0.069

Neutral

(source)

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

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over