rs104895137
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000243.3(MEFV):c.1260+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,609,952 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 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00031 ( 1 hom. )
Consequence
MEFV
NM_000243.3 intron
NM_000243.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.809
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 16-3249421-G-A is Benign according to our data. Variant chr16-3249421-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=4, not_provided=1, Benign=3}. Variant chr16-3249421-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.1260+10C>T | intron_variant | ENST00000219596.6 | NP_000234.1 | |||
MEFV | NM_001198536.2 | c.627+10C>T | intron_variant | NP_001185465.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEFV | ENST00000219596.6 | c.1260+10C>T | intron_variant | 1 | NM_000243.3 | ENSP00000219596.1 |
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000570 AC: 141AN: 247282Hom.: 1 AF XY: 0.000522 AC XY: 70AN XY: 134062
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GnomAD4 exome AF: 0.000308 AC: 449AN: 1457596Hom.: 1 Cov.: 31 AF XY: 0.000307 AC XY: 223AN XY: 725226
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GnomAD4 genome AF: 0.000341 AC: 52AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial Mediterranean fever Uncertain:1Benign:2Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 13, 2020 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 14, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 16, 2022 | Variant summary: MEFV c.1260+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 247282 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00057 vs 0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1260+10C>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign n=2, like benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. - |
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | MEFV NM_000243.2 exon 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 09, 2021 | - - |
Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Sep 30, 2020 | MEFV NM_000243.2 exon 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at