8-124539251-G-C

Variant names:

• chr8-124539251-G-C
• rs1390326483
• NM_005005.3:c.65G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005005.3(NDUFB9):​c.65G>C​(p.Arg22Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22W) has been classified as Uncertain significance.

• 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: 5.12
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB9	NM_005005.3	MANE Select	c.65G>C	p.Arg22Pro	missense	Exon 1 of 4	NP_004996.1	Q9Y6M9
	NDUFB9	NM_001311168.2		c.65G>C	p.Arg22Pro	missense	Exon 1 of 4	NP_001298097.1	E9PH64
	NDUFB9	NM_001278646.2		c.-63G>C		5_prime_UTR	Exon 1 of 4	NP_001265575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB9	ENST00000276689.8	TSL:1 MANE Select	c.65G>C	p.Arg22Pro	missense	Exon 1 of 4	ENSP00000276689.3	Q9Y6M9
	NDUFB9	ENST00000901305.1		c.65G>C	p.Arg22Pro	missense	Exon 1 of 5	ENSP00000571364.1
	NDUFB9	ENST00000518008.5	TSL:2	c.65G>C	p.Arg22Pro	missense	Exon 1 of 3	ENSP00000428282.1	E7EWZ0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251016 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.57
MutPred		0.65		Loss of MoRF binding (P = 0.0099)
MVP		0.94
MPC		0.97
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.92
gMVP		0.88
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1390326483; hg19: chr8-125551492;