chr8-124549829-G-C

Variant names:

• chr8-124549829-G-C
• rs774020236
• NM_005005.3:c.477G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005005.3(NDUFB9):​c.477G>C​(p.Lys159Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K159K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NDUFB9 NM_005005.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• 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]

NDUFB9 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 24

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3354004).

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.477G>C	p.Lys159Asn	missense	Exon 4 of 4	NP_004996.1	Q9Y6M9
	NDUFB9	NM_001311168.2		c.444G>C	p.Lys148Asn	missense	Exon 4 of 4	NP_001298097.1	E9PH64
	NDUFB9	NM_001278646.2		c.348G>C	p.Lys116Asn	missense	Exon 4 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.477G>C	p.Lys159Asn	missense	Exon 4 of 4	ENSP00000276689.3	Q9Y6M9
	NDUFB9	ENST00000901305.1		c.576G>C	p.Lys192Asn	missense	Exon 5 of 5	ENSP00000571364.1
	NDUFB9	ENST00000928469.1		c.474G>C	p.Lys158Asn	missense	Exon 4 of 4	ENSP00000598528.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112004

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

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.42	B
Vest4		0.37
MutPred		0.17		Loss of methylation at K159 (P = 0.0023)
MVP		0.83
MPC		0.60
ClinPred		0.92	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.60
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs774020236; hg19: chr8-125562070;