rs104895105
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000243.3(MEFV):c.1432C>T(p.His478Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/21 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: 33)
Consequence
MEFV
NM_000243.3 missense
NM_000243.3 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: -0.0980
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP6
?
Variant 16-3247171-G-A is Benign according to our data. Variant chr16-3247171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2557.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.1432C>T | p.His478Tyr | missense_variant | 5/10 | ENST00000219596.6 | |
MEFV | NM_001198536.2 | c.799C>T | p.His267Tyr | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEFV | ENST00000219596.6 | c.1432C>T | p.His478Tyr | missense_variant | 5/10 | 1 | NM_000243.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 65
GnomAD4 exome
Cov.:
65
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial Mediterranean fever Uncertain:3Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 08, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2557). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 14679589). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 478 of the MEFV protein (p.His478Tyr). - |
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, autosomal dominant Pathogenic:1Benign:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2022 | Reported in published literature in individuals from a family with an autosomal dominant periodic inflammatory disorder with renal AA amyloidosis and was found to exclusively co-segregate with the disease in all individuals tested (Aldea et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19479870, 22614345, 18328141, 29260407, 23844200, 23031807, 27225717, 15024744, 14679589) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | MEFV: PM2, PP1:Moderate, PP4, BP4 - |
Acute febrile neutrophilic dermatosis 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;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;D;T
Polyphen
P;.;.;.
Vest4
MutPred
Gain of phosphorylation at H478 (P = 0.054);.;.;.;
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