8-124539527-G-C

Position:

• chr8-124539527-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005005.3(NDUFB9):​c.101+240G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 544,148 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (8 hom.)
• Consequence: NDUFB9 NM_005005.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.142

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=-0.84).
• BP6: Variant 8-124539527-G-C is Benign according to our data. Variant chr8-124539527-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1316727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1703/152326) while in subpopulation AFR AF= 0.0385 (1601/41572). AF 95% confidence interval is 0.0369. There are 28 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.101+240G>C		intron_variant		ENST00000276689.8	NP_004996.1
NDUFB9	NM_001278645.2	c.-33+240G>C		intron_variant			NP_001265574.1
NDUFB9	NM_001278646.2	c.-27+240G>C		intron_variant			NP_001265575.1
NDUFB9	NM_001311168.2	c.101+240G>C		intron_variant			NP_001298097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.101+240G>C		intron_variant		1	NM_005005.3	ENSP00000276689	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1697 AN: 152208 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00148 AC: 581 AN: 391822 Hom.: 8 AF XY: 0.00131 AC XY: 270 AN XY: 205568

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.0000408

Gnomad4 NFE exome AF: 0.0000896

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0112 AC: 1703 AN: 152326 Hom.: 28 Cov.: 33 AF XY: 0.0112 AC XY: 831 AN XY: 74500

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00798 Hom.: 1

Bravo AF: 0.0131

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.43

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: rs7011005; hg19: chr8-125551768;