8-124539123-A-G

Position:

• chr8-124539123-A-G

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.-64A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,612,478 control chromosomes in the GnomAD database, including 13,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (789 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12387 hom.)
• Consequence: NDUFB9 NM_005005.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0340

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]

TATDN1 (HGNC:24220): (TatD DNase domain containing 1) Predicted to enable 3'-5'-exodeoxyribonuclease activity. Predicted to be involved in DNA metabolic process and nucleic acid phosphodiester bond hydrolysis. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 8-124539123-A-G is Benign according to our data. Variant chr8-124539123-A-G is described in ClinVar as [Benign]. Clinvar id is 671738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.-64A>G		5_prime_UTR_variant	1/4	ENST00000276689.8	NP_004996.1
TATDN1	NM_032026.4			upstream_gene_variant		ENST00000276692.11	NP_114415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.-64A>G		5_prime_UTR_variant	1/4	1	NM_005005.3	ENSP00000276689	P1
TATDN1	ENST00000276692.11			upstream_gene_variant		1	NM_032026.4	ENSP00000276692	P1

Frequencies

GnomAD3 genomes AF: 0.0899 AC: 13686 AN: 152218 Hom.: 789 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.0967

GnomAD4 exome AF: 0.125 AC: 182020 AN: 1460142 Hom.: 12387 Cov.: 32 AF XY: 0.124 AC XY: 90048 AN XY: 726210

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0918

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.0898 AC: 13687 AN: 152336 Hom.: 789 Cov.: 33 AF XY: 0.0910 AC XY: 6777 AN XY: 74488

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.0639

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.0952

Alfa AF: 0.114 Hom.: 136

Bravo AF: 0.0826

Asia WGS AF: 0.0400 AC: 139 AN: 3478

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 14, 2018	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_noAF	Benign	-0.96
CADD	Benign	7.0
DANN	Benign	0.45

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: rs34681068; hg19: chr8-125551364;