rs2070080
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000143.4(FH):c.1302C>T(p.Cys434Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,608,838 control chromosomes in the GnomAD database, including 473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.029 ( 273 hom., cov: 31)
Exomes 𝑓: 0.0031 ( 200 hom. )
Consequence
FH
NM_000143.4 synonymous
NM_000143.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.224
Genes affected
FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 1-241500525-G-A is Benign according to our data. Variant chr1-241500525-G-A is described in ClinVar as [Benign]. Clinvar id is 137372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241500525-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.224 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.1302C>T | p.Cys434Cys | synonymous_variant | 9/10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.1302C>T | p.Cys434Cys | synonymous_variant | 9/10 | 1 | NM_000143.4 | ENSP00000355518.4 |
Frequencies
GnomAD3 genomes AF: 0.0293 AC: 4417AN: 150652Hom.: 270 Cov.: 31
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GnomAD3 exomes AF: 0.00762 AC: 1914AN: 251324Hom.: 92 AF XY: 0.00538 AC XY: 731AN XY: 135818
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GnomAD4 exome AF: 0.00310 AC: 4522AN: 1458070Hom.: 200 Cov.: 32 AF XY: 0.00272 AC XY: 1974AN XY: 725288
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GnomAD4 genome AF: 0.0294 AC: 4439AN: 150768Hom.: 273 Cov.: 31 AF XY: 0.0284 AC XY: 2092AN XY: 73580
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ClinVar
Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2013 | 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 17, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2016 | Variant summary: The c.1302C>T variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts polymorphism outcome for this variant. 4/5 splice-tools in Alamut predict that this variant does not affect normal splicing. ESE finder predicts changes of binding motifs for RNA splicing enhancers. This variant is found in 1162/121368 control chromosomes (64 homozygotes) at a frequency of 0.0095742, which significantly exceeds the maximal expected frequency of a pathogenic allele (0.0000025), suggesting this variant is a benign polymorphism. In addition, multiple clinical laboratory/reputable database classified this variant as benign. Taken together, this variant was classified as benign. - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 04, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 18, 2023 | - - |
Hereditary leiomyomatosis and renal cell cancer Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
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. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Fumarase deficiency Benign:2
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. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 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. - |
Computational scores
Source:
Name
Calibrated prediction
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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