rs104895087
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000243.3(MEFV):c.2024G>A(p.Ser675Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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).
Frequency
Genomes: not found (cov: 32)
Consequence
MEFV
NM_000243.3 missense
NM_000243.3 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.258
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 Uncertain_significance. Variant got 3 ACMG points.
PM1
In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38077906).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.2024G>A | p.Ser675Asn | missense_variant | 10/10 | ENST00000219596.6 | NP_000234.1 | |
MEFV | NM_001198536.2 | c.*228G>A | 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.2024G>A | p.Ser675Asn | missense_variant | 10/10 | 1 | NM_000243.3 | ENSP00000219596 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial Mediterranean fever Uncertain:2Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
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 exon 10 p.Ser675Asn (c.2024G>A): This variant has been reported in the literature in 1 individual with a suspicion of Familial Mediterranean Fever (FMF); of note, this individual was heterozygous and an additional disease causing variant was not identified (Dode 2000 PMID:10842288). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:97478). This variant amino acid Asparagine (Asn) is present in >20 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
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 | Dec 05, 2017 | MEFV NM_000243.2 exon 10 p.Ser675Asn (c.2024G>A): This variant has been reported in the literature in 1 individual with a suspicion of Familial Mediterranean Fever (FMF); of note, this individual was heterozygous and an additional disease causing variant was not identified (Dode 2000 PMID:10842288). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:97478). This variant amino acid Asparagine (Asn) is present in >20 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MutPred
Loss of glycosylation at S675 (P = 0.018);.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at