chr5-218352-A-G
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004168.4(SDHA):c.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,458,606 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 57 hom., cov: 34)
Exomes 𝑓: 0.0015 ( 44 hom. )
Consequence
SDHA
NM_004168.4 5_prime_UTR
NM_004168.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.05
Genes affected
SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 5-218352-A-G is Benign according to our data. Variant chr5-218352-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-218352-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.-4A>G | 5_prime_UTR_variant | 1/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.-4A>G | 5_prime_UTR_variant | 1/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0153 AC: 2324AN: 152118Hom.: 56 Cov.: 34
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GnomAD3 exomes AF: 0.00296 AC: 332AN: 112288Hom.: 10 AF XY: 0.00230 AC XY: 149AN XY: 64914
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GnomAD4 exome AF: 0.00148 AC: 1935AN: 1306380Hom.: 44 Cov.: 31 AF XY: 0.00137 AC XY: 885AN XY: 644652
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GnomAD4 genome AF: 0.0153 AC: 2332AN: 152226Hom.: 57 Cov.: 34 AF XY: 0.0149 AC XY: 1109AN XY: 74428
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2016 | 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 14, 2021 | - - |
Mitochondrial complex II deficiency, nuclear type 1 Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hereditary pheochromocytoma-paraganglioma 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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