8-124539144-A-G

Position:

• chr8-124539144-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005005.3(NDUFB9):​c.-43A>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 0.00517 in 1,613,300 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (30 hom.)
• Consequence: NDUFB9 NM_005005.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.401

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-124539144-A-G is Benign according to our data. Variant chr8-124539144-A-G is described in ClinVar as [Benign]. Clinvar id is 138470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.-43A>G		5_prime_UTR_variant	1/4	ENST00000276689.8	NP_004996.1
NDUFB9	NM_001278645.2	c.-176A>G		5_prime_UTR_variant	1/4		NP_001265574.1
NDUFB9	NM_001278646.2	c.-170A>G		5_prime_UTR_variant	1/4		NP_001265575.1
NDUFB9	NM_001311168.2	c.-43A>G		5_prime_UTR_variant	1/4		NP_001298097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.-43A>G		5_prime_UTR_variant	1/4	1	NM_005005.3	ENSP00000276689	P1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152264 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.00440 AC: 1103 AN: 250630 Hom.: 4 AF XY: 0.00433 AC XY: 588 AN XY: 135734

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00593

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00528 AC: 7712 AN: 1460918 Hom.: 30 Cov.: 32 AF XY: 0.00518 AC XY: 3767 AN XY: 726794

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00566

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.00413 AC: 629 AN: 152382 Hom.: 1 Cov.: 33 AF XY: 0.00370 AC XY: 276 AN XY: 74520

Gnomad4 AFR AF: 0.00264

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00610 Hom.: 1

Bravo AF: 0.00449

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2013

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. -

not provided Benign:1

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	-0.87
CADD	Benign	6.1
DANN	Benign	0.63

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: rs140365193; hg19: chr8-125551385;