16-19067667-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_SupportingPM2PP5

The NM_016138.5(COQ7):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COQ7
NM_016138.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 2.55

Variant links:

Genes affected

COQ7 (HGNC:2244): (coenzyme Q7, hydroxylase) The protein encoded by this gene is similar to a mitochondrial di-iron containing hydroxylase in Saccharomyces cerevisiae that is involved with ubiquinone biosynthesis. Mutations in the yeast gene lead to slower development and longer life span. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

COQ7 links:

COQ7-DT (HGNC:55362): (COQ7 divergent transcript)

COQ7-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 39 codons. Genomic position: 19071969. Lost 0.176 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-19067667-G-T is Pathogenic according to our data. Variant chr16-19067667-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1463095.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ7	NM_016138.5 link	c.3G>T	p.Met1?	start_lost	Exon 1 of 6	ENST00000321998.10	NP_057222.2	Q99807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ7	ENST00000321998.10 link	c.3G>T	p.Met1?	start_lost	Exon 1 of 6	1	NM_016138.5	ENSP00000322316.5		Q99807-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 9

Pathogenic:2

Dec 20, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alternate start codon. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001463095). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 31, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary coenzyme Q10 deficiency 8

Pathogenic:1Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 01-04-2022 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the COQ7 mRNA. The next in-frame methionine is located at codon 39. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COQ7-related conditions. ClinVar contains an entry for this variant (Variation ID: 1463095). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.14

T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.74

PROVEAN

Benign

-0.63

N;N

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.85

P;P

Vest4

0.84

MutPred

0.99

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.52

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.47

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