rs121913659

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_007103.4(NDUFV1):​c.1268C>G​(p.Thr423Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T423M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NDUFV1
NM_007103.4 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.79
Variant links:
Genes affected
NDUFV1 (HGNC:7716): (NADH:ubiquinone oxidoreductase core subunit V1) The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-67612225-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDUFV1NM_007103.4 linkc.1268C>G p.Thr423Arg missense_variant Exon 9 of 10 ENST00000322776.11 NP_009034.2 P49821-1E5KNH5
NDUFV1NM_001166102.2 linkc.1241C>G p.Thr414Arg missense_variant Exon 9 of 10 NP_001159574.1 P49821-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDUFV1ENST00000322776.11 linkc.1268C>G p.Thr423Arg missense_variant Exon 9 of 10 1 NM_007103.4 ENSP00000322450.6 P49821-1

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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D;D;D;.;D
Eigen
Pathogenic
0.79
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H;H;.;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.5
.;D;D;D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D
Polyphen
0.97
D;D;.;D;D
Vest4
0.90, 0.90, 0.89, 0.91
MutPred
0.71
Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);.;.;.;
MVP
0.98
MPC
0.92
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.98
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-67379696; API