rs2230892
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_005006.7(NDUFS1):c.1371G>A(p.Ser457=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,613,868 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.011 ( 21 hom., cov: 33)
Exomes 𝑓: 0.016 ( 244 hom. )
Consequence
NDUFS1
NM_005006.7 synonymous
NM_005006.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.99
Genes affected
NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
?
Variant 2-206138506-C-T is Benign according to our data. Variant chr2-206138506-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138480.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr2-206138506-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.99 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1702/152244) while in subpopulation NFE AF= 0.0174 (1182/68028). AF 95% confidence interval is 0.0166. There are 21 homozygotes in gnomad4. There are 774 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 21 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS1 | NM_005006.7 | c.1371G>A | p.Ser457= | synonymous_variant | 13/19 | ENST00000233190.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS1 | ENST00000233190.11 | c.1371G>A | p.Ser457= | synonymous_variant | 13/19 | 1 | NM_005006.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0112 AC: 1702AN: 152126Hom.: 21 Cov.: 33
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GnomAD3 exomes AF: 0.0113 AC: 2837AN: 251472Hom.: 32 AF XY: 0.0114 AC XY: 1544AN XY: 135908
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GnomAD4 exome AF: 0.0162 AC: 23741AN: 1461624Hom.: 244 Cov.: 32 AF XY: 0.0161 AC XY: 11737AN XY: 727124
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GnomAD4 genome ? AF: 0.0112 AC: 1702AN: 152244Hom.: 21 Cov.: 33 AF XY: 0.0104 AC XY: 774AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 11, 2016 | - - |
Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Leigh syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Mitochondrial complex 1 deficiency, nuclear type 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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