14-73953419-AT-ATT

Variant names:

• chr14-73953419-A-AT
• rs745746077
• NM_182476.3:c.164-12dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_182476.3(COQ6):​c.164-12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,351,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COQ6 NM_182476.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

Genes affected

COQ6 (HGNC:20233): (coenzyme Q6, monooxygenase) The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. Knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis. Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2012]

COQ6 Gene-Disease associations (from GenCC):

• familial steroid-resistant nephrotic syndrome with sensorineural deafness

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 14-73953419-A-AT is Benign according to our data. Variant chr14-73953419-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	NM_182476.3	MANE Select	c.164-12dupT		intron	N/A	NP_872282.1
	COQ6	NM_001425255.1		c.164-12dupT		intron	N/A	NP_001412184.1
	COQ6	NM_182480.3		c.89-12dupT		intron	N/A	NP_872286.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	ENST00000334571.7	TSL:1 MANE Select	c.164-16_164-15insT		intron	N/A	ENSP00000333946.2
	COQ6	ENST00000554193.5	TSL:1	n.187-16_187-15insT		intron	N/A
	COQ6	ENST00000554341.6	TSL:1	n.89-16_89-15insT		intron	N/A	ENSP00000450736.2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00177 AC: 424 AN: 239374 AF XY: 0.00161

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00498

Gnomad ASJ exome AF: 0.000723

Gnomad EAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.000705

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00421 AC: 5685 AN: 1351542 Hom.: 0 Cov.: 29 AF XY: 0.00395 AC XY: 2665 AN XY: 673932

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

African (AFR) AF: 0.00822 AC: 244 AN: 29670

American (AMR) AF: 0.00580 AC: 237 AN: 40832

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 58 AN: 24734

East Asian (EAS) AF: 0.00871 AC: 297 AN: 34108

South Asian (SAS) AF: 0.00305 AC: 246 AN: 80680

European-Finnish (FIN) AF: 0.00141 AC: 72 AN: 51106

Middle Eastern (MID) AF: 0.00127 AC: 7 AN: 5512

European-Non Finnish (NFE) AF: 0.00415 AC: 4275 AN: 1029210

Other (OTH) AF: 0.00447 AC: 249 AN: 55690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00625 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial steroid-resistant nephrotic syndrome with sensorineural deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	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: rs745746077; hg19: chr14-74420122; COSMIC: COSV53179502; COSMIC: COSV53179502;