chr16-3249705-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000243.3(MEFV):c.986G>A(p.Arg329His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,764 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 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: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 10 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:5O:3

Conservation

PhyloP100: -1.76

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]

MEFV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004503727).

BP6

Variant 16-3249705-C-T is Benign according to our data. Variant chr16-3249705-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9, not_provided=3}. Variant chr16-3249705-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 10 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.986G>A	p.Arg329His	missense_variant	Exon 3 of 10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 link	c.353G>A	p.Arg118His	missense_variant	Exon 2 of 9		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.986G>A	p.Arg329His	missense_variant	Exon 3 of 10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00163

AC:

405

AN:

248242

Hom.:

AF XY:

0.00178

AC XY:

240

AN XY:

134486

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00238

AC:

3471

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1734

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0113

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00254

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00131

AC:

199

AN:

152324

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00214

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00161

AC:

195

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:5Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV: BP4, BS1 -

Feb 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.986G>A; p.Arg329His variant (rs104895112) has been described in the literature in several individuals affected with familial Mediterranean fever (FMF), atypical FMF, or fibromyalgia (Lainka 2012, Feng 2009, Portincasa 2013, Yao 2016). This variant is listed in ClinVar (Variation ID: 97557) and is found in the general population with an overall allele frequency of 0.16% (441/279644 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at position 329 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.166). Due to the wide range of phenyotypes and lack of functional data, the significance of the p.Arg329His variant is uncertain at this time. References: Lainka E et al. Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population. Eur J Pediatr. 2012 Dec;171(12):1775-85. PMID: 22903357. Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009. 4(12):e8480. PMID: 20041150. Portincasa P et al. Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder. Eur J Clin Invest. 2013 Dec;43(12):1314-27. PMID: 24117178. Yao Q et al. Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. Semin Arthritis Rheum. 2016 Apr;45(5):633-7. PMID: 26620106. -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with a second variant (phase unknown) in multiple unrelated individuals with familial Mediterranean fever (PMID: 29260407, 27838405, 30755392); Reported in the heterozygous state in multiple unrelated individuals with familial Mediterranean fever (PMID: 26620106, 20041150, 22903357); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26554556, 26247045, 22903357, 23010357, 23325590, 24117178, 20041150, 29178647, 23867542, 22337722, 37928541, 26620106, 29408806, 32271453, 27838405, 29260407, 23070486, 31989427, 37941861, 30755392, 35156637) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial Mediterranean fever

Uncertain:3Benign:1Other:3

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 28, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 09-17-2019 by LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

May 04, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant

Uncertain:1

Dec 08, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV NM_000243.2 exon 3 p.Arg329His (c.986G>A): This variant has been reported in the literature in at least 8 individuals with features of Familial Mediterranean Fever (FMF) as heterozygous, at least 1 of whom were identified to have a pathogenic variant in MEFV in trans (p.Met694Ile) (Berdelli 2012 PMID:n/a, Kumpfel 2012 PMID:22337722, Lainka 2012 PMID:22903357, Pauwels 2013 PMID:23325590, Yao 2016 PMID:26620106). In addition, this variant was identified in at least 1 individual with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.2% (63/30562) of South Asian alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299705-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97557). This variant amino acid Histidine (His) is present in >30 species including mammals 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 conflicting and insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autoinflammatory syndrome

Uncertain:1

Jan 20, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant

Uncertain:1

Sep 28, 2020

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV NM_000243.2 exon 3 p.Arg329His (c.986G>A): This variant has been reported in the literature in at least 8 individuals with features of Familial Mediterranean Fever (FMF) as heterozygous, at least 1 of whom were identified to have a pathogenic variant in MEFV in trans (p.Met694Ile) (Berdelli 2012 PMID:n/a, Kumpfel 2012 PMID:22337722, Lainka 2012 PMID:22903357, Pauwels 2013 PMID:23325590, Yao 2016 PMID:26620106). In addition, this variant was identified in at least 1 individual with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.2% (63/30562) of South Asian alleles amd 1.1% (111/10,054) of Ashkenazi Jewish alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299705-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97557). This variant amino acid Histidine (His) is present in >30 species including mammals 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 conflicting and insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

Feb 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEFV c.986G>A (p.Arg329His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249988 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not higher than predicted for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0016 vs 0.022), allowing no conclusion about variant significance. c.986G>A, has been reported in the literature in patients in association with FMF, atypical FMF, MS and fibromyalgia (e.g. Feng_2009, Kuempfel_2012, Berdeli_2012, Pauwels_2013, Heshin-Bekenstein_2015, Yao_2016, Balta_2018, Zhang_2018). The phenotypic variability seen with this variant and genotypic information are not clearly specific to FMF, and at least some of these reported FMF patients were not responsive to colchicine therapy (Hashkes_2012). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Recently, the International Study Group for Systemic Autoinflammatory Diseases (INSIAD) involving experts on hereditary recurrent fever genetics, provided a classification of likely benign with a validated status for c.986G>A (Van Gijn_2018). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=8). At-least one submitter has re-classified this variant as likely benign. Another submitter has cited overlapping evidence utilized in the context of our evaluation. We have followed this variant for over four years and previously classified it as a VUS. In our review of published evidence spanning over 10 years (2009-2019), the majority of evidence appears to point toward a non-pathogenic outcome however more data is required to conclusively determine the clinical consequences of this variant. Therefore, based on the evidence outlined above, this variant in isolation is re-classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.37

DANN

Benign

0.26

DEOGEN2

Benign

0.27

T;.;.;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.42

N;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

3.6

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.81

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.090

MVP

0.39

MPC

0.14

ClinPred

0.0030

GERP RS

-8.6

Varity_R

0.017

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over