chr16-3243405-C-T

Position:

• chr16-3243405-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000243.3(MEFV):​c.2082G>A​(p.Met694Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. M694K) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 O:1
• Conservation: PhyloP100: -1.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 7) in uniprot entity MEFV_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000243.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243406-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 16-3243405-C-T is Pathogenic according to our data. Variant chr16-3243405-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243405-C-T is described in Lovd as [Pathogenic]. Variant chr16-3243405-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2082G>A	p.Met694Ile	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*286G>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.2082G>A	p.Met694Ile	missense_variant	10/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251490 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000383 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Pathogenic:14 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV variant status is uncertain. Sources cited for classification include the following: PMID 9288094, 10612841, 16378925, 19863562, 11938447, and 16378925. Classification of NM_000243.2(MEFV):c.2082G>A(M694I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with familial Mediterranean fever (examples: Majeed 2005 PMID: 15942916, Moradian 2014 PMID: 23907647). It has been reported in ClinVar ( Variation ID 2539) and has been identified in 1/316 Middle Eastern and 3/5196 East Asian chromosomes (among other population where the variant freqency is lower) by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant affects the level of IL8 secretion (Sugiyama 2014 PMID: 24318677). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). This variant is present in population databases (rs28940578, gnomAD 0.05%). This missense change has been observed in individuals with familial Mediterranean fever (PMID: 10787449, 12064853, 15168590, 15805719, 20051664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2539). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781020, 10364520, 12064853, 21290976, 22037353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 08, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 18, 2022	PS3, PM1, PM5, PM2, PP5, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 11, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16378925) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12064853). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538,VCV000449657, PMID:23031807,NULL,9288758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not provided Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2023	PP1, PM1, PM3_very_strong, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 28, 2022	The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2020	Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 02, 2023	- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 19, 2017	MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been reported in several publications, including a GeneReviews entry describing this variant as disease causing (Shothat 2016 PMID:20301405). This variant is present in 17/12674 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28940578). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2539). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 25, 2017	- -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 25, 2022

- -

MEFV-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2024

The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Cazeneuve et al. 1999. PubMed ID: 10364520). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	7.3
DANN	Benign	0.64
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.13	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.96	L;.;.
MutationTaster	Benign	6.0e-12	A;A;A;A
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.79	P;.;.
Vest4		0.30
MutPred		0.88		Loss of catalytic residue at M694 (P = 0.0144);.;.;
MVP		0.65
MPC		0.15
ClinPred		0.40	T
GERP RS		-1.8
Varity_R		0.36
gMVP		0.29

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

Other links and lift over

dbSNP: rs28940578; hg19: chr16-3293405;