rs104895079

chr16-3254567-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000243.3(MEFV):c.501G>C(p.Glu167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,571,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:7 O:1
• Conservation: PhyloP100: 0.300

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 16-3254567-C-G is Pathogenic according to our data. Variant chr16-3254567-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2543.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=4, not_provided=1, Pathogenic=1}. Variant chr16-3254567-C-G is described in Lovd as [Likely_pathogenic]. Variant chr16-3254567-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.501G>C	p.Glu167Asp	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+1744G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.501G>C	p.Glu167Asp	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152218 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: 0.0000440 AC: 8 AN: 181710 Hom.: 0 AF XY: 0.0000397 AC XY: 4 AN XY: 100690

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: 0.0000919

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.0000303 AC: 43 AN: 1419548 Hom.: 0 Cov.: 37 AF XY: 0.0000284 AC XY: 20 AN XY: 703922

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: 0.0000311

Gnomad4 OTH exome AF: 0.000119

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

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: 0.000116 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000849 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2022	The MEFV c.501G>C; p.Glu167Asp variant (rs104895079) is reported in the homozygous and compound heterozygous state in affected individuals (Ceylan 2012, Papa 2017, Ustek 2008) and is often found on the same chromosome as c.1437C>G; p.Phe479Leu (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015). However, the c.1437C>G; p.Phe479Leu variant was not detected in this individual. The.501G>C; p.Glu167Asp variant was described as likely pathogenic by a panel of experts (Van Gijn 2018) and is listed in the ClinVar database (Variation ID: 2543). The variant is described in the general population with an overall allele frequency of 0.005% (10/213,066 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.535). Due to the uncertainty regarding the pathogenicity of the p.Glu167Asp variant when found individually, the clinical significance of the p.Glu167Asp variant is uncertain at this time. 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. Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. 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 Papa R et al A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. Ustek D et al. MEFV gene 3'-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2008 Jul-Aug;26(4 Suppl 50):S72-6. [OR] 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	Occurs often with the F479L variant, usually proven to be on the same allele (in cis) (Bernot A et al., 1998; Bozgeyik E et al., 2020; Bonyadi M et al., 2009; Ceylan GG et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25708585, 22614345, 9668175, 32199921, 19863562, 17489852, 24469716, 10090880, 29178647, 18609258, 15024744, 11175300, 25393764) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial Mediterranean fever Pathogenic:3 Uncertain:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 167 of the MEFV protein (p.Glu167Asp). This variant is present in population databases (rs104895079, gnomAD 0.01%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Phe479Leu variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 12180071, 25708585, 25393764, 21413889, 26351556, 24469716, 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: 2543). ClinVar contains an entry for this variant (Variation ID: 2543). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Familial Mediterranean fever, autosomal dominant Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2022	- -

Autoinflammatory syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 09, 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.501G>C (p.Glu167Asp) results in a 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 4.4e-05 in 182315 control chromosomes (gnomAD, exomes dataset). c.501G>C (p.E167D) is often observed in the same chromosome (in cis) with c.1437C>G (p.Phe479Leu) forming a complex allele p.[E167D;F479L]. Nevertheless, E167D has also been reported in the literature as a variant in isolation in homozygous or compound heterozygous state, in a few individuals affected with Familial Mediterranean Fever (e.g. Ceylan_2012, Papa_2017, Ustek_2008, Bozgeyik_2020). These data indicate that the variant is likely to be associated with disease. In 2012, an international consortium of experts reached a consensus (as part of an agreed set of best practice guidelines) to test for 14 MEFV variants, nine of which were considered pathogenic (including E167D) and 5 of unknown significance (Shinar_2012). In addition, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) agreed in a consensus classification of (provisional) likely pathogenic for the variant (Van Gijn_2018). 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 citing overlapping evidence utilized in the context of this evaluation (Pathogenic/Likely pathogenic, n=5; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	6.4e-10	A;A;A;A
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.014	D
Sift4G	Benign	0.17	T
Polyphen		0.60	P
Vest4		0.31
MutPred		0.69		Loss of solvent accessibility (P = 0.0635);
MVP		0.85
MPC		0.29
ClinPred		0.10	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.38

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: rs104895079; hg19: chr16-3304567;