rs104895085

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000219596.6(MEFV):​c.1958G>A​(p.Arg653His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MEFV
ENST00000219596.6 missense

Scores

2
17

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:2

Conservation

PhyloP100: 0.522
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-3243529-C-T is Pathogenic according to our data. Variant chr16-3243529-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MEFVNM_000243.3 linkuse as main transcriptc.1958G>A p.Arg653His missense_variant 10/10 ENST00000219596.6 NP_000234.1
MEFVNM_001198536.2 linkuse as main transcriptc.*162G>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.1958G>A p.Arg653His missense_variant 10/101 NM_000243.3 ENSP00000219596 P3O15553-2

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251200
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135764
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461590
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000138
Hom.:
0
Bravo
AF:
0.0000604
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10Uncertain:1Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial Mediterranean fever Pathogenic:5Uncertain:1Other:2
Likely pathogenic, no assertion criteria providedclinical testingCounsylMar 15, 2019- -
Uncertain significance, flagged submissionclinical testingMendelicsMay 28, 2019- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterJun 08, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 653 of the MEFV protein (p.Arg653His). This variant is present in population databases (rs104895085, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 11470495, 16378925, 19479870, 21413889, 24469716, 29159471, 31989427; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2553). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 23, 2017Variant summary: The MEFV c.1958G>A (p.Arg653His) variant located in the SPRY domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 2/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 6/121204 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple publications have cited the variant in affected individuals in whom a second mutation not identified. Of note, this variant was reported in one affected individual who met the Tel-Hashomer criteria for a diagnosis of MEFV as a compound heterozygote along with p.M694V. The unaffected mother and brother were carriers for the variant of interest. In addition, Booty_2009 reports a clinically diagnosed FMF affected sib-pair that each carry only the variant of interest following a comprehensive search for a second mutation in the MEFV gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, although no in-vitro or in-vivo functional studies supporting a damaging outcome for this variant have been reported, the ascertained evidence has been weighted to classify this variant as Pathogenic. -
not provided, no classification providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2001- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 02, 2016The R653H pathogenic variant in the MEFV that has been previously reported in association with Familial Mediterranean Fever (FMF) (Schaner et al., 2001; Timmann et al., 2001; Booty et al., 2009; Lazarin et al., 2013). It has also been observed in patients with juvenile idiopathic arthritis (Comak et al., 2013). The R653 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R653H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, a missense variant in a nearby residue (E656A) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 14, 2014- -
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 18, 2021The MEFV c.1958G>A; p.Arg653His variant (rs104895085) has been described in the heterozygous state in several individuals with a clinical diagnosis of familial Mediterranean fever and at least once in the compound heterozygous state in an individual with an additional pathogenic variant (Berdeli 2011, Botty 2009, Comak 2013, Jeske 2013, Oztuzcu 2014, Schaner 2001, Shinar 2007, Timmann 2001). The variant is reported in the ClinVar database (Variation ID: 2553) and is listed in the general population with an overall allele frequency of 0.0035% (10/282,580 alleles) in the Genome Aggregation Database. The arginine at codon 653 occurs in the SPRY domain, is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). However, most pathogenic MEFV variants occur in the SPRY domain (Manukyan 2016). Based on available information, this variant is classified as likely pathogenic. References: Berdeli A et al. Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey? Genet Test Mol Biomarkers. 2011 Jul-Aug;15(7-8):475-82. Booty MG et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009 Jun;60(6):1851-61. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Jeske M et al. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. Klin Padiatr. 2013 Nov;225(6):325-30 Manukyan G and Aminov R Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever. Front. Microbiol. 2016 7:456. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. Schaner P et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet. 2001 Mar;27(3):318-21. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. Timmann C et al. Two novel mutations R653H and E230K in the Mediterranean fever gene associated with disease. Mutat Res. 2001 Aug 8;479(1-2):235-9. -
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalDec 12, 2019- -
Familial Mediterranean fever, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
9.2
DANN
Benign
0.10
DEOGEN2
Benign
0.29
T;.;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.56
T;T;T
M_CAP
Benign
0.0050
T
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-2.6
N;.;.
MutationTaster
Benign
3.2e-12
A;A;A;A
PrimateAI
Benign
0.30
T
PROVEAN
Benign
4.7
N;N;N
REVEL
Uncertain
0.34
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.45
MVP
0.32
MPC
0.14
ClinPred
0.024
T
GERP RS
1.6
Varity_R
0.39
gMVP
0.30

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: rs104895085; hg19: chr16-3293529; COSMIC: COSV105004010; COSMIC: COSV105004010; API