rs11848954

Variant names:

• chr14-73949995-C-G
• rs11848954
• NM_152445.3:c.32G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182480.3(COQ6):​c.-98C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,392 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (114 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (180 hom.)
• Consequence: COQ6 NM_182480.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.129
• Publications: 4 publications found

Genes affected

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]

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):

• primary coenzyme Q10 deficiency 8

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• familial steroid-resistant nephrotic syndrome with sensorineural deafness

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023985505).
• BP6: Variant 14-73949995-C-G is Benign according to our data. Variant chr14-73949995-C-G is described in ClinVar as Benign. ClinVar VariationId is 1234053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0691 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182480.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM161B	NM_152445.3	MANE Select	c.32G>C	p.Gly11Ala	missense	Exon 1 of 9	NP_689658.3	Q96MY7-1
	COQ6	NM_182480.3		c.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_872286.2	Q9Y2Z9-3
	COQ6	NM_001425258.1		c.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001412187.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM161B	ENST00000286544.5	TSL:1 MANE Select	c.32G>C	p.Gly11Ala	missense	Exon 1 of 9	ENSP00000286544.4	Q96MY7-1
	COQ6	ENST00000554341.6	TSL:1	n.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000450736.2	G3V2L5
	COQ6	ENST00000554341.6	TSL:1	n.-98C>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000450736.2	G3V2L5

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3916 AN: 152156 Hom.: 114 Cov.: 32

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0136 AC: 3400 AN: 249948 AF XY: 0.0140

Gnomad AFR exome AF: 0.0710

Gnomad AMR exome AF: 0.00972

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000428

Gnomad NFE exome AF: 0.00608

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.00853 AC: 12468 AN: 1461118 Hom.: 180 Cov.: 32 AF XY: 0.00909 AC XY: 6608 AN XY: 726912

African (AFR) AF: 0.0725 AC: 2426 AN: 33480

American (AMR) AF: 0.0108 AC: 481 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 529 AN: 26134

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39698

South Asian (SAS) AF: 0.0296 AC: 2552 AN: 86258

European-Finnish (FIN) AF: 0.000266 AC: 14 AN: 52660

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.00484 AC: 5384 AN: 1112008

Other (OTH) AF: 0.0141 AC: 852 AN: 60388

GnomAD4 genome AF: 0.0258 AC: 3927 AN: 152274 Hom.: 114 Cov.: 32 AF XY: 0.0255 AC XY: 1896 AN XY: 74464

African (AFR) AF: 0.0713 AC: 2962 AN: 41562

American (AMR) AF: 0.0161 AC: 246 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0296 AC: 143 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00610 AC: 415 AN: 68012

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.0103 Hom.: 25

Bravo AF: 0.0274

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0642 AC: 283

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.0149 AC: 1814

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00782

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.4
DANN	Benign	0.95
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.13
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.022
Sift	Benign	0.18	T
Sift4G	Benign	1.0	T
Vest4		0.11
MPC		0.074
ClinPred		0.014	T
GERP RS		1.9
PromoterAI		0.015	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs11848954; hg19: chr14-74416698; COSMIC: COSV53178478; COSMIC: COSV53178478;