chr8-124539195-C-A

Variant names:

• chr8-124539195-C-A
• NM_005005.3:c.9C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005005.3(NDUFB9):​c.9C>A​(p.Phe3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFB9 NM_005005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048722535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 4	ENST00000276689.8	NP_004996.1
TATDN1	NM_032026.4	c.-149G>T		upstream_gene_variant		ENST00000276692.11	NP_114415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 4	1	NM_005005.3	ENSP00000276689.3
TATDN1	ENST00000276692.11	c.-149G>T		upstream_gene_variant		1	NM_032026.4	ENSP00000276692.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.59
DANN	Benign	0.73
DEOGEN2	Benign	0.056	.;T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.29	T;T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.42	.;N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.69	.;T;T;T
Sift4G	Benign	0.83	.;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.11, 0.13, 0.14
MutPred		0.24		Loss of catalytic residue at F3 (P = 0.0443);Loss of catalytic residue at F3 (P = 0.0443);Loss of catalytic residue at F3 (P = 0.0443);Loss of catalytic residue at F3 (P = 0.0443);
MVP		0.55
MPC		0.27
ClinPred		0.033	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-125551436;