14-73950129-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000554341.6(COQ6):c.37G>T(p.Val13Phe) variant causes a missense, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,598,948 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (29 hom.)
• Consequence: COQ6 ENST00000554341.6 missense, NMD_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.201

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]

FAM161B (HGNC:19854): (FAM161 centrosomal protein B) Predicted to be involved in cilium organization. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002567917).
• BP6: Variant 14-73950129-G-T is Benign according to our data. Variant chr14-73950129-G-T is described in ClinVar as [Benign]. Clinvar id is 136985.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00902 (1374/152348) while in subpopulation AFR AF= 0.0315 (1311/41584). AF 95% confidence interval is 0.0301. There are 9 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM161B	NM_152445.3			upstream_gene_variant		ENST00000286544.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ6	ENST00000554341.6	c.37G>T	p.Val13Phe	missense_variant, NMD_transcript_variant	1/11	1
FAM161B	ENST00000651776.1	c.87C>A	p.Asp29Glu	missense_variant	1/9
COQ6	ENST00000394026.8	c.37G>T	p.Val13Phe	missense_variant	1/12	2
FAM161B	ENST00000286544.5			upstream_gene_variant		1	NM_152445.3	P1

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1370 AN: 152230 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00240 AC: 543 AN: 226478 Hom.: 6 AF XY: 0.00193 AC XY: 241 AN XY: 125182

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000767

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.00103 AC: 1489 AN: 1446600 Hom.: 29 Cov.: 32 AF XY: 0.000914 AC XY: 658 AN XY: 720078

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00902 AC: 1374 AN: 152348 Hom.: 9 Cov.: 33 AF XY: 0.00891 AC XY: 664 AN XY: 74500

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00395 Hom.: 3

Bravo AF: 0.0104

ExAC AF: 0.00282 AC: 340

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	4.1
Dann	Uncertain	0.99
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.015
Sift	Pathogenic	0.0	D
Vest4		0.040
MutPred		0.26		Gain of ubiquitination at K31 (P = 0.0594);
MVP		0.030
MPC		0.060
ClinPred		0.012	T
GERP RS		-1.5

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

Other links and lift over

dbSNP: rs111833521; hg19: chr14-74416832;