rs104895083

chr16-3247166-G-Cchr16-3247166-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000243.3(MEFV):c.1437C>G(p.Phe479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,046 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:3 O:1
• Conservation: PhyloP100: -0.0880

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3247166-G-C is Pathogenic according to our data. Variant chr16-3247166-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2545.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Uncertain_significance=3, Likely_pathogenic=3, not_provided=1}. Variant chr16-3247166-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1437C>G	p.Phe479Leu	missense_variant	5/10	ENST00000219596.6
MEFV	NM_001198536.2	c.804C>G	p.Phe268Leu	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1437C>G	p.Phe479Leu	missense_variant	5/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251496 Hom.: 0 AF XY: 0.0000368 AC XY: 5 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: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461888 Hom.: 0 Cov.: 65 AF XY: 0.0000275 AC XY: 20 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000306

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Pathogenic:5 Uncertain:2 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 479 of the MEFV protein (p.Phe479Leu). This variant is present in population databases (rs104895083, gnomAD 0.009%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Glu167Asp variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 25708585, 25393764, 22975760, 23907647, 26351556, 29363386, 29178647). In some of these individuals, an additional MEFV variant was not identified on the opposite allele, while in others, multiple additional MEFV variants were identified. Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 2545). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	The p.Phe479Leu variant is a well established pathogenic variant and it has been reported in the homozygous, heterozygous and compound heterozygous state (with other well known pathogenic MEFV variants) in numerous individuals with Familial mediteranean fever (FMF) (personal communication Pr Serge Amselem, Medlej-Hashim 2000 PMID: 10737992); frequently it has been reported in cis with p.Glu167Asp and this complex allele is one of the most common pathogenic MEFV variants in Cypriot populations (Neocleous 2015 PMID: 25393764 ). The p.Phe479Leu variant has been reported in ClinVar (Variation ID: 2545)and it has been identified in 4/68034 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial mediteranean fever (FMF). ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/282890 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Statistically enriched in patients compared to ethnically matched controls. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2020	The MEFV c.[501G>C;1437C>G]; p.[Glu167Asp;Phe479Leu] variant is a complex allele consisting of two changes on the same chromosome, p.Glu167Asp and p.Phe479Leu. Although p.Phe479Leu has been reported on its own, to the best of our knowledge p.Glu167Asp has only been reported as a complex allele with p.Phe479Leu. The complex variant has been published in the literature in both the homozygous and compound heterozygous state in individuals affected with familial Mediterranean fever (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015) and is one of the most common pathogenic MEFV variants in the Cypriot populations (Neocleous 2015). Based on available information, this variant is considered to be pathogenic. References: 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. Bonyadi M et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet. 2009 Nov;76(5):477-80. Mansour I et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet. 2001 Jan;9(1):51-5. Neocleous V et al. Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Ann Hum Genet. 2015 Jan;79(1):20-7 -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 11, 2017	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 19, 2023

- -

Autoinflammatory syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 03, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 06, 2023

Variant summary: MEFV c.1437C>G (p.Phe479Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (4e-05 vs 0.022), allowing no conclusion about variant significance. c.1437C>G has been widely reported in the literature in individuals affected with Familial Mediterranean Fever. It is often reported in the same chromosome (in cis) with c.501G>C (p.Glu167Asp) in many studies. However, the limited extent of genotyping or unclear specification of phase preclude a traceable association of this specific variant in isolation to the phenotype of Familial Mediterranean Fever (example, PMID: 15951859, 31598713, 31989427, 9668175, 35098403, 29040788, 19253030, 20485448, 15146467, 25393764, 34328662, 17566872, 33726481, 31646357). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=8; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	0.39
Dann	Benign	0.27
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.5	N;.;.;.
MutationTaster	Benign	9.1e-7	A;A;A;A
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.8	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.050
MutPred		0.76		Loss of helix (P = 0.1706);.;.;.;
MVP		0.25
MPC		0.13
ClinPred		0.93	D
GERP RS		-0.14
Varity_R		0.21
gMVP		0.091

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: rs104895083; hg19: chr16-3297166;