rs104895093
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000243.3(MEFV):c.2076_2078delAAT(p.Ile692del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MEFV
NM_000243.3 disruptive_inframe_deletion
NM_000243.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.94
Genes affected
MEFV (HGNC:6998): (MEFV innate immunity regulator, pyrin) This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a strand (size 7) in uniprot entity MEFV_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000243.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000243.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-3243408-CATT-C is Pathogenic according to our data. Variant chr16-3243408-CATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243408-CATT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.2076_2078delAAT | p.Ile692del | disruptive_inframe_deletion | 10/10 | ENST00000219596.6 | NP_000234.1 | |
MEFV | NM_001198536.2 | c.*280_*282delAAT | 3_prime_UTR_variant | 9/9 | NP_001185465.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEFV | ENST00000219596.6 | c.2076_2078delAAT | p.Ile692del | disruptive_inframe_deletion | 10/10 | 1 | NM_000243.3 | ENSP00000219596.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727236
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial Mediterranean fever Pathogenic:4Uncertain:1Other:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 15, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2023 | Variant summary: MEFV c.2076_2078delAAT (p.Ile692del) results in an in-frame deletion that is predicted to remove one amino acid, Ile692, from the SPRY domain (IPR003877) of the encoded protein. The variant allele was found at a frequency of 7.9e-06 in 252200 control chromosomes (gnomAD and publications). c.2076_2078delAAT has been reported in the literature in the compound heterozygous and heterozygous state in multiple individuals affected with Familial Mediterranean Fever across several countries, including cases where it has been observed in trans with a pathogenic variant (e.g. Bernot_1998, Tchernitchko_2003, Medlej-Hashim_2005, Chaabouni_2007, Singh-Grewal_2007, Sabbagh_2008, El Garf_2010, Jardour_2010, Berdeli_2011, Salehzadeh_2015, Ait-Idir_2017). These data indicate that the variant is likely to be associated with disease. However, this variant mostly associates in cis with p.E148Q, a common variant with controversial pathogenicity and/or low penetrance and thus, there are fewer cases where the variant has been observed in isolation from which to definitively determine its association to the disease phenotype. At least one publication reports experimental evidence evaluating an impact of the variant on protein function (Honda_2021) and found that the variant was more responsive to TcdA- and UCN-01-induced cell death compared to the WT protein, suggesting it has an effect on protein function, yet the significance of this finding in a clinical context are not clear. Therefore this study does not allow for unequivocal conclusions about the variant effect. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=5)/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic until further evidence (i.e. homozygous occurrences in patients, cosegregation of the variant with FMF and/or additional functional studies) is available. - |
Uncertain significance, flagged submission | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 26, 2019 | This variant, c.2076_2078del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Ile692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial mediterranean fever (PMID: 29047407, 9668175, 21246368, 15018633, 22019805, 29379228, 25648235, 21413889, 28302131, 14578331, 19253030, 17566872). ClinVar contains an entry for this variant (Variation ID: 97485). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | nframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000097485, PMID:9668175). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). The variant is observed to be in trans with the other variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1998 | - - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2019 | The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 29, 2023 | The MEFV c.2076_2078delAAT; p.Ile692del variant (rs104895093), is reported in the literature in multiple individuals affected with familial Mediterranean fever (FMF) (Aoki 2022, Bernot 1998, Platt 2021, Salehzadeh 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 97485), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single isoleucine residue leaving the rest of the protein in-frame. Functional analyses demonstrate increased cell death compared to wild-type, similar to other known pathogenic variants (Aoki 2022, Honda 2021). This variant affects a residue in the conserved region of the B30.2 domain, which contains pathogenic MEFV variants associated with the most severe FMF symptoms (Moradian 2017). Based on available information, the p.Ile692del variant is considered to be pathogenic. References: Aoki M et al. Case Report: A Pediatric Case of Familial Mediterranean Fever Concurrent With Autoimmune Hepatitis. Front Immunol. 2022 Jun 24;13:917398. PMID: 35812376. Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PMID: 9668175. Honda Y et al. Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. J Clin Immunol. 2021 Aug;41(6):1187-1197. PMID: 33733382. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Platt CD et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021 Feb;147(2):723-726. PMID: 32888943. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. PMID: 25648235. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2023 | Published functional studies demonstrate this variant has a deleterious effect on protein function (Honda et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19253030, 22975760, 23907647, 9668175, 10737995, 25648235, 26892483, 29543225, 32888943, 35812376, 19302049, 29379228, 28302131, 29047407, 17566872, 33733382) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 16, 2015 | - - |
Familial Mediterranean fever, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2023 | - - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2022 | - - |
Computational scores
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