rs141228574

Positions:

chr9-128332233-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_016035.5(COQ4):c.483G>C(p.Glu161Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,613,374 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 85 hom. )

Consequence

COQ4
NM_016035.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.884

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:

COQ4 (HGNC:):

COQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (size 234) in uniprot entity COQ4_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in NM_016035.5

BP4

Computational evidence support a benign effect (MetaRNN=0.018062353).

BP6

Variant 9-128332233-G-C is Benign according to our data. Variant chr9-128332233-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 380493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332233-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00555 (845/152292) while in subpopulation SAS AF= 0.0104 (50/4830). AF 95% confidence interval is 0.00807. There are 6 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ4	NM_016035.5 linkuse as main transcript	c.483G>C	p.Glu161Asp	missense_variant	5/7	ENST00000300452.8	NP_057119.3	Q9Y3A0-1
COQ4	XM_047423449.1 linkuse as main transcript	c.*83G>C		3_prime_UTR_variant	4/4		XP_047279405.1
COQ4	NM_001305942.2 linkuse as main transcript	c.*3-1241G>C		intron_variant			NP_001292871.2	A0A024R890
COQ4	XM_017014792.2 linkuse as main transcript	c.*3-617G>C		intron_variant			XP_016870281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8 linkuse as main transcript	c.483G>C	p.Glu161Asp	missense_variant	5/7	1	NM_016035.5	ENSP00000300452.3		Q9Y3A0-1
COQ4	ENST00000461102.1 linkuse as main transcript	n.1822G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00809

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00629

AC:

1568

AN:

249250

Hom.:

AF XY:

0.00641

AC XY:

865

AN XY:

134878

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00279

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00933

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00862

Gnomad OTH exome

AF:

0.00755

GnomAD4 exome

AF:

0.00838

AC:

12239

AN:

1461082

Hom.:

Cov.:

AF XY:

0.00849

AC XY:

6168

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.0113

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00919

Gnomad4 OTH exome

AF:

0.00780

GnomAD4 genome

AF:

0.00555

AC:

845

AN:

152292

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00809

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00812

Hom.:

Bravo

AF:

0.00603

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00647

AC:

785

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00837

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	COQ4: BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.49

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.45

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.90

MutPred

0.93

Loss of stability (P = 0.142);

MVP

0.71

MPC

1.2

ClinPred

0.058

GERP RS

2.8

Varity_R

0.67

gMVP

0.75

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

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