8-124539195-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005005.3(NDUFB9):​c.9C>G​(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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F3F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NDUFB9
NM_005005.3 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.17

Publications

0 publications found
Variant links:
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]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.045562744).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDUFB9NM_005005.3 linkc.9C>G p.Phe3Leu missense_variant Exon 1 of 4 ENST00000276689.8 NP_004996.1 Q9Y6M9
TATDN1NM_032026.4 linkc.-149G>C upstream_gene_variant ENST00000276692.11 NP_114415.1 Q6P1N9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDUFB9ENST00000276689.8 linkc.9C>G p.Phe3Leu missense_variant Exon 1 of 4 1 NM_005005.3 ENSP00000276689.3 Q9Y6M9
TATDN1ENST00000276692.11 linkc.-149G>C upstream_gene_variant 1 NM_032026.4 ENSP00000276692.6 Q6P1N9-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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
0.62
DANN
Benign
0.69
DEOGEN2
Benign
0.056
.;T;.;T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.075
N
LIST_S2
Benign
0.29
T;T;T;T
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.046
T;T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-0.42
.;N;.;.
PhyloP100
-2.2
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
0.032
T
GERP RS
-4.1
PromoterAI
0.0022
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.082
gMVP
0.34
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs765755463; hg19: chr8-125551436; API