rs752513525
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3PP5_ModerateBS2
The NM_015965.7(NDUFA13):c.170G>A(p.Arg57His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,940 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 Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
NDUFA13
NM_015965.7 missense
NM_015965.7 missense
Scores
4
11
3
Clinical Significance
Conservation
PhyloP100: 7.40
Genes affected
NDUFA13 (HGNC:17194): (NADH:ubiquinone oxidoreductase subunit A13) This gene encodes a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain. The protein is required for complex I assembly and electron transfer activity. The protein binds the signal transducers and activators of transcription 3 (STAT3) transcription factor, and can function as a tumor suppressor. The human protein purified from mitochondria migrates at approximately 16 kDa. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
?
In a chain NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 (size 142) in uniprot entity NDUAD_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_015965.7
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.801
PP5
?
Variant 19-19526257-G-A is Pathogenic according to our data. Variant chr19-19526257-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132643.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-19526257-G-A is described in Lovd as [Likely_pathogenic].
BS2
?
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFA13 | NM_015965.7 | c.170G>A | p.Arg57His | missense_variant | 2/5 | ENST00000507754.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFA13 | ENST00000507754.9 | c.170G>A | p.Arg57His | missense_variant | 2/5 | 1 | NM_015965.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250456Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135704
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461704Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727148
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74384
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 28 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 28 (MIM#618249) (PMIDs: 25901006, 32722639). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GRIM-19 family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed as homozygous in two siblings with developmental delay, seizures, hypotonia and optic atrophy. The variant was confirmed to be hetrozygous in their unaffected parents and an unaffected sibling (PMID: 25901006). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blot experiments in fibroblasts from patients homozygous for this variant showed reduced protein levels for NDUFA13 and other CI subunits. Blue native page experiments in these cells also showed a reduction in the abundance of CI and the CI, CIII, CIV supramolecular complex (PMID: 25901006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Mitochondrial complex I deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | research | INSERM U1051, Institut des Neurosciences de Montpellier | May 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D;D;D;D;N
PROVEAN
Uncertain
D;.;.;N
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
T;T;T;T
Polyphen
D;.;.;.
Vest4
MutPred
Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at