rs104895087

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

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:1

Conservation

PhyloP100: 0.258
Variant links:
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
MEFVNM_000243.3 linkuse as main transcriptc.2024G>A p.Ser675Asn missense_variant 10/10 ENST00000219596.6 NP_000234.1
MEFVNM_001198536.2 linkuse as main transcriptc.*228G>A 3_prime_UTR_variant 9/9 NP_001185465.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MEFVENST00000219596.6 linkuse as main transcriptc.2024G>A p.Ser675Asn missense_variant 10/101 NM_000243.3 ENSP00000219596 P3O15553-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabFeb 08, 2023- -
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021MEFV 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 submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoDec 05, 2017MEFV 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 submitterclinical testingGenome-Nilou LabFeb 08, 2023- -
Familial Mediterranean fever, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabFeb 08, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
2.0
DANN
Benign
0.87
DEOGEN2
Benign
0.34
T;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.078
N
LIST_S2
Benign
0.060
T;T;T
M_CAP
Benign
0.0094
T
MetaRNN
Benign
0.38
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.14
N;.;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.14
Sift
Benign
0.21
T;T;T
Sift4G
Benign
0.35
T;T;T
Polyphen
0.0010
B;.;.
Vest4
0.078
MutPred
0.76
Loss of glycosylation at S675 (P = 0.018);.;.;
MVP
0.58
MPC
0.11
ClinPred
0.058
T
GERP RS
0.094
Varity_R
0.24
gMVP
0.075

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104895087; hg19: chr16-3293463; API