16-3254532-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PM5BP4_StrongBP6
The NM_000243.3(MEFV):c.536G>A(p.Ser179Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,555,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S179I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000243.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.536G>A | p.Ser179Asn | missense_variant | 2/10 | ENST00000219596.6 | |
MEFV | NM_001198536.2 | c.277+1779G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEFV | ENST00000219596.6 | c.536G>A | p.Ser179Asn | missense_variant | 2/10 | 1 | NM_000243.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000281 AC: 44AN: 156324Hom.: 0 AF XY: 0.000394 AC XY: 34AN XY: 86284
GnomAD4 exome AF: 0.000105 AC: 147AN: 1403068Hom.: 1 Cov.: 36 AF XY: 0.000157 AC XY: 109AN XY: 694008
GnomAD4 genome ? AF: 0.0000656 AC: 10AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74484
ClinVar
Submissions by phenotype
Familial Mediterranean fever Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 179 of the MEFV protein (p.Ser179Asn). This variant is present in population databases (rs104895125, gnomAD 0.2%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 20721559, 29579081). ClinVar contains an entry for this variant (Variation ID: 664952). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 19, 2023 | The MEFV c.536G>A (p.Ser179Asn) missense variant results in the substitution of serine at amino acid position 179 with asparagine. This variant has been reported in an individual with familial Mediterranean fever (FMF) who also carried another missense variant (phase unknown) (PMID: 20721559). The c.536G>A variant was also identified in a homozygous state in two individuals with rheumatic heart disease. This variant resides between the PYD and BBox domain and 3-D protein modelling show that the c.536G>A variant impacts the protein structure and conformation as compared to normal protein (DOI: 10.4172/2155-9899.1000382). A different missense change at the same amino acid residue has also been reported in a compound heterozygous state with a pathogenic variant in a father and son with FMF (PMID: 14636645). This variant is reported in the Genome Aggregation Database in nine alleles at a frequency of 0.00186 in the South Asian population (version 3.1.2). Based on the available evidence, the c.536G>A (p.Ser179Asn) variant is classified as a variant of uncertain significance for familial Mediterranean fever. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 14, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Acute febrile neutrophilic dermatosis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Familial Mediterranean fever, autosomal dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at