8-124542846-A-C

Position:

• chr8-124542846-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005005.3(NDUFB9):​c.102-241A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 263,958 control chromosomes in the GnomAD database, including 4,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2124 hom., cov: 23)
  • Exomes 𝑓: 0.15 (2424 hom.)
• Consequence: NDUFB9 NM_005005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0320

Genes affected

NDUFB9 (HGNC:7704): (NADH:ubiquinone oxidoreductase subunit B9) The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-124542846-A-C is Benign according to our data. Variant chr8-124542846-A-C is described in ClinVar as [Benign]. Clinvar id is 1278403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.102-241A>C		intron_variant		ENST00000276689.8	NP_004996.1
NDUFB9	NM_001278645.2	c.-32-276A>C		intron_variant			NP_001265574.1
NDUFB9	NM_001278646.2	c.-26-243A>C		intron_variant			NP_001265575.1
NDUFB9	NM_001311168.2	c.102-274A>C		intron_variant			NP_001298097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.102-241A>C		intron_variant		1	NM_005005.3	ENSP00000276689	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 21988 AN: 118904 Hom.: 2124 Cov.: 23

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.152 AC: 22019 AN: 145038 Hom.: 2424 AF XY: 0.151 AC XY: 11343 AN XY: 75046

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0395

Gnomad4 SAS exome AF: 0.0975

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.185 AC: 21985 AN: 118920 Hom.: 2124 Cov.: 23 AF XY: 0.185 AC XY: 10303 AN XY: 55688

Gnomad4 AFR AF: 0.0554

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.214

Alfa AF: 0.166 Hom.: 1085

Bravo AF: 0.162

Asia WGS AF: 0.111 AC: 385 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.61

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: rs12550827; hg19: chr8-125555087;