8-124539250-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005005.3(NDUFB9):​c.64C>T​(p.Arg22Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NDUFB9
NM_005005.3 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDUFB9NM_005005.3 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 4 ENST00000276689.8 NP_004996.1 Q9Y6M9
TATDN1NM_032026.4 linkc.-204G>A 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.64C>T p.Arg22Trp missense_variant Exon 1 of 4 1 NM_005005.3 ENSP00000276689.3 Q9Y6M9
TATDN1ENST00000276692.11 linkc.-204G>A upstream_gene_variant 1 NM_032026.4 ENSP00000276692.6 Q6P1N9-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251016
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135822
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.64C>T (p.R22W) alteration is located in exon 1 (coding exon 1) of the NDUFB9 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the arginine (R) at amino acid position 22 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Jul 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the NDUFB9 protein (p.Arg22Trp). This variant is present in population databases (rs759625380, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NDUFB9-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
.;D;.;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Benign
0.73
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.76
D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Pathogenic
3.1
.;M;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-4.4
.;D;D;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Uncertain
0.0030
.;D;D;D
Polyphen
1.0
.;D;.;.
Vest4
0.49, 0.49, 0.54
MutPred
0.62
Loss of methylation at K21 (P = 0.0558);Loss of methylation at K21 (P = 0.0558);Loss of methylation at K21 (P = 0.0558);Loss of methylation at K21 (P = 0.0558);
MVP
0.96
MPC
0.29
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.63
gMVP
0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759625380; hg19: chr8-125551491; API