rs104895093

Positions:

• chr16-3243408-CATT-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000243.3(MEFV):​c.2076_2078delAAT​(p.Ile692del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEFV NM_000243.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:2
• Conservation: PhyloP100: 2.94

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• PM4: Nonframeshift variant in NON repetitive region in NM_000243.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-3243408-CATT-C is Pathogenic according to our data. Variant chr16-3243408-CATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243408-CATT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2076_2078delAAT	p.Ile692del	disruptive_inframe_deletion	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*280_*282delAAT		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.2076_2078delAAT	p.Ile692del	disruptive_inframe_deletion	10/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Pathogenic:4 Uncertain:1 Other:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 15, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2023	Variant summary: MEFV c.2076_2078delAAT (p.Ile692del) results in an in-frame deletion that is predicted to remove one amino acid, Ile692, from the SPRY domain (IPR003877) of the encoded protein. The variant allele was found at a frequency of 7.9e-06 in 252200 control chromosomes (gnomAD and publications). c.2076_2078delAAT has been reported in the literature in the compound heterozygous and heterozygous state in multiple individuals affected with Familial Mediterranean Fever across several countries, including cases where it has been observed in trans with a pathogenic variant (e.g. Bernot_1998, Tchernitchko_2003, Medlej-Hashim_2005, Chaabouni_2007, Singh-Grewal_2007, Sabbagh_2008, El Garf_2010, Jardour_2010, Berdeli_2011, Salehzadeh_2015, Ait-Idir_2017). These data indicate that the variant is likely to be associated with disease. However, this variant mostly associates in cis with p.E148Q, a common variant with controversial pathogenicity and/or low penetrance and thus, there are fewer cases where the variant has been observed in isolation from which to definitively determine its association to the disease phenotype. At least one publication reports experimental evidence evaluating an impact of the variant on protein function (Honda_2021) and found that the variant was more responsive to TcdA- and UCN-01-induced cell death compared to the WT protein, suggesting it has an effect on protein function, yet the significance of this finding in a clinical context are not clear. Therefore this study does not allow for unequivocal conclusions about the variant effect. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=5)/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic until further evidence (i.e. homozygous occurrences in patients, cosegregation of the variant with FMF and/or additional functional studies) is available. -
Uncertain significance, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2019	This variant, c.2076_2078del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Ile692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial mediterranean fever (PMID: 29047407, 9668175, 21246368, 15018633, 22019805, 29379228, 25648235, 21413889, 28302131, 14578331, 19253030, 17566872). ClinVar contains an entry for this variant (Variation ID: 97485). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	nframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000097485, PMID:9668175). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). The variant is observed to be in trans with the other variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2019	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2023	The MEFV c.2076_2078delAAT; p.Ile692del variant (rs104895093), is reported in the literature in multiple individuals affected with familial Mediterranean fever (FMF) (Aoki 2022, Bernot 1998, Platt 2021, Salehzadeh 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 97485), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single isoleucine residue leaving the rest of the protein in-frame. Functional analyses demonstrate increased cell death compared to wild-type, similar to other known pathogenic variants (Aoki 2022, Honda 2021). This variant affects a residue in the conserved region of the B30.2 domain, which contains pathogenic MEFV variants associated with the most severe FMF symptoms (Moradian 2017). Based on available information, the p.Ile692del variant is considered to be pathogenic. References: Aoki M et al. Case Report: A Pediatric Case of Familial Mediterranean Fever Concurrent With Autoimmune Hepatitis. Front Immunol. 2022 Jun 24;13:917398. PMID: 35812376. Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PMID: 9668175. Honda Y et al. Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. J Clin Immunol. 2021 Aug;41(6):1187-1197. PMID: 33733382. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Platt CD et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021 Feb;147(2):723-726. PMID: 32888943. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. PMID: 25648235. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2023	Published functional studies demonstrate this variant has a deleterious effect on protein function (Honda et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19253030, 22975760, 23907647, 9668175, 10737995, 25648235, 26892483, 29543225, 32888943, 35812376, 19302049, 29379228, 28302131, 29047407, 17566872, 33733382) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 16, 2015	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2023

- -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

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: rs104895093; hg19: chr16-3293408;