rs10195

Positions:

• chr8-124549788-C-G
• chr8-124549788-C-T

Variant summary

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

The ENST00000276689.8(NDUFB9):​c.436C>G​(p.Pro146Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB9 ENST00000276689.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.509

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]

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=0.017438889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB9	NM_005005.3	c.436C>G	p.Pro146Ala	missense_variant	4/4	ENST00000276689.8	NP_004996.1
NDUFB9	NM_001311168.2	c.403C>G	p.Pro135Ala	missense_variant	4/4		NP_001298097.1
NDUFB9	NM_001278646.2	c.307C>G	p.Pro103Ala	missense_variant	4/4		NP_001265575.1
NDUFB9	NM_001278645.2	c.268C>G	p.Pro90Ala	missense_variant	4/4		NP_001265574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB9	ENST00000276689.8	c.436C>G	p.Pro146Ala	missense_variant	4/4	1	NM_005005.3	ENSP00000276689	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.89
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.069
MutPred		0.16		Loss of catalytic residue at P145 (P = 0.0144);.;
MVP		0.41
MPC		0.22
ClinPred		0.059	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.21

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: rs10195; hg19: chr8-125562029;