rs104895091

chr16-3243403-TTCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000243.3(MEFV):c.2081_2083del(p.Met694del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MEFV NM_000243.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:2
• Conservation: PhyloP100: 0.187

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain 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 16-3243403-TTCA-T is Pathogenic according to our data. Variant chr16-3243403-TTCA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2556.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2, not_provided=2}. Variant chr16-3243403-TTCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.2081_2083del	p.Met694del	inframe_deletion	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*285_*287del		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.2081_2083del	p.Met694del	inframe_deletion	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461878 Hom.: 0 AF XY: 0.00000825 AC XY: 6 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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2016	Variant summary: The MEFV c.2081_2083delTGA (p.Met694del) variant involves an in-frame deletion of three nucleotides. One in silico tool predicts a benign outcome for this variant. The variant is absent in 121410 control chromosomes while it was reported in several FMF patients in heterozygosity indicating a dominant inheritance. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2022	This variant, c.2081_2083del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Met694del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs104895091, gnomAD 0.002%). This variant has been observed in individual(s) with Familial Mediterranean Fever (PMID: 10024914, 10787449, 19479870, 21246368, 29047407). ClinVar contains an entry for this variant (Variation ID: 2556). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MEFV function (PMID: 33733382). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 10, 2023

The MEFV c.2081_2083del; p.Met694del variant (rs104895091) is reported in the literature in multiple individuals and families with a clinical diagnosis of familial Mediterranean fever; individuals of northern European ancestry often had clinical symptoms without an additional pathogenic variant (Booth 2000, Booty 2009, Rowczenio 2017), whereas two individuals of Moroccan ancestry had an additional pathogenic variant consistent with autosomal recessive inheritance (Belmahi 2012). This variant is also reported in ClinVar (Variation ID: 2556), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single methionine residue leaving the rest of the protein in-frame. Considering available information, this variant is classified as pathogenic. References: Belmahi L et al. MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. Rheumatol Int. 2012 Apr;32(4):981-4. PMID: 21246368. Booth DR et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM. 2000 Apr;93(4):217-21. PMID: 10787449. 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. PMID: 19479870. Rowczenio DM et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford). 2017 Feb;56(2):209-213. PMID: 27150194. -

Familial Mediterranean fever, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2000

- -

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: rs104895091; hg19: chr16-3293403;