rs567
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1
The NM_002495.4(NDUFS4):c.*46G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.466 in 1,335,210 control chromosomes in the GnomAD database, including 148,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.42 ( 14389 hom., cov: 32)
Exomes 𝑓: 0.47 ( 134134 hom. )
Consequence
NDUFS4
NM_002495.4 3_prime_UTR
NM_002495.4 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.27).
BP6
Variant 5-53683267-G-A is Benign according to our data. Variant chr5-53683267-G-A is described in ClinVar as [Benign]. Clinvar id is 353892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS4 | NM_002495.4 | c.*46G>A | 3_prime_UTR_variant | 5/5 | ENST00000296684.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS4 | ENST00000296684.10 | c.*46G>A | 3_prime_UTR_variant | 5/5 | 1 | NM_002495.4 | P1 | ||
NDUFS4 | ENST00000506974.5 | c.*350G>A | 3_prime_UTR_variant, NMD_transcript_variant | 6/6 | 1 | ||||
NDUFS4 | ENST00000506765.1 | c.*137G>A | 3_prime_UTR_variant | 4/4 | 2 | ||||
NDUFS4 | ENST00000507026.5 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.423 AC: 64128AN: 151692Hom.: 14388 Cov.: 32
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GnomAD3 exomes AF: 0.457 AC: 113385AN: 248356Hom.: 26796 AF XY: 0.458 AC XY: 61547AN XY: 134356
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GnomAD4 exome AF: 0.471 AC: 557935AN: 1183400Hom.: 134134 Cov.: 17 AF XY: 0.472 AC XY: 284077AN XY: 602120
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GnomAD4 genome AF: 0.423 AC: 64146AN: 151810Hom.: 14389 Cov.: 32 AF XY: 0.425 AC XY: 31492AN XY: 74164
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial complex I deficiency, nuclear type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Leigh syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
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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