9-128323147-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_016035.5(COQ4):c.202G>C(p.Asp68His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000965 in 1,585,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D68N) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

COQ4
NM_016035.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.39

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_016035.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-128323147-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685665.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 9-128323147-G-C is Pathogenic according to our data. Variant chr9-128323147-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128323147-G-C is described in Lovd as [Likely_pathogenic]. Variant chr9-128323147-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5 link	c.202G>C	p.Asp68His	missense_variant, splice_region_variant	Exon 2 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.202G>C	p.Asp68His	missense_variant, splice_region_variant	Exon 2 of 7	1	NM_016035.5	ENSP00000300452.3	Q9Y3A0-1
COQ4	ENST00000609948.1 link	c.202G>C	p.Gly68Arg	missense_variant	Exon 2 of 2	2		ENSP00000477292.1	V9GZ09
COQ4	ENST00000372875.3 link	c.202G>C	p.Asp68His	missense_variant, splice_region_variant	Exon 2 of 4	2		ENSP00000361966.3	Q5T4B9
COQ4	ENST00000608951.5 link	c.202G>C	p.Asp68His	missense_variant, splice_region_variant	Exon 2 of 3	2		ENSP00000476323.1	V9GY32

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000432

AC:

AN:

208574

Hom.:

AF XY:

0.0000341

AC XY:

AN XY:

117468

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.0000998

AC:

143

AN:

1433454

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

712040

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.000102

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.0000846

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000595

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Pathogenic:3

Jun 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COQ4 c.202G>C (p.Asp68His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant is located at the last nucleotide of exon 2, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, and one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.3e-05 in 208574 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.202G>C has been reported in the literature in several compound heterozygous individuals, including two siblings, affected with Neonatal Encephalomyopathy-Cardiomyopathy Distress Syndrome (e.g., Chung_2015, Helbig_2016, Farwell-Hagman_2017, deCastro_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26185144, 27513193, 26795593, 32718099). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 27, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 68 of the COQ4 protein (p.Asp68His). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs758522459, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency and/or multiple congenital anomalies (PMID: 26185144, 26795593, 27513193, 32718099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267347). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jul 05, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202G>C (p.D68H) alteration is located in exon 2 of the COQ4 gene. This alteration results from a G to C substitution at nucleotide position 202, causing the aspartic acid (D) at amino acid position 68 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (10/239964) total alleles studied. The highest observed frequency was 0.02% (1/6244) of Other alleles. This alteration has been detected in conjunction with a pathogenic COQ4 alteration in multiple individuals with COQ4-related primary coenzyme Q deficiency (Chung, 2015; Barbosa-Gouveia, 2021). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Jan 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3_strong, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;T;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Uncertain

-0.0065

MutationAssessor

Pathogenic

3.8

H;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.1

D;.;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.94

MutPred

0.80

Gain of MoRF binding (P = 0.0821);Gain of MoRF binding (P = 0.0821);Gain of MoRF binding (P = 0.0821);

MVP

0.83

MPC

1.3

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.95

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over