rs751633537
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_004168.4(SDHA):c.-7A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,455,416 control chromosomes in the GnomAD database, including 1 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 0.00078 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0010 ( 1 hom. )
Consequence
SDHA
NM_004168.4 5_prime_UTR
NM_004168.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.187
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 5-218349-A-C is Benign according to our data. Variant chr5-218349-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=1, Uncertain_significance=5}. Variant chr5-218349-A-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000782 (119/152270) while in subpopulation NFE AF= 0.00118 (80/67998). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SDHA | NM_004168.4 | c.-7A>C | 5_prime_UTR_variant | 1/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SDHA | ENST00000264932.11 | c.-7A>C | 5_prime_UTR_variant | 1/15 | 1 | NM_004168.4 | ENSP00000264932 | P1 |
Frequencies
GnomAD3 genomes 0.000789 AC: 120AN: 152162Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000666 AC: 72AN: 108066Hom.: 0 AF XY: 0.000800 AC XY: 50AN XY: 62516
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GnomAD4 exome AF: 0.00103 AC: 1341AN: 1303146Hom.: 1 Cov.: 31 AF XY: 0.00105 AC XY: 673AN XY: 642938
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GnomAD4 genome 0.000782 AC: 119AN: 152270Hom.: 0 Cov.: 34 AF XY: 0.000672 AC XY: 50AN XY: 74454
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 01, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | SDHA: BS1 - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2017 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 07, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2015 | The c.-7A>C alteration is located in the 5' untranslated region (5'UTR) of the SDHA gene. This alteration consists of a A to C substitution nucleotides upstream from the first translated codon. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 02, 2020 | - - |
Paragangliomas 5 Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 31, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 21, 2023 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Leigh syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | - - |
Hereditary pheochromocytoma-paraganglioma Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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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