rs104895144

chr16-3254293-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000243.3(MEFV):c.775A>G(p.Ile259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,100 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).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3 O:1
• Conservation: PhyloP100: -0.202

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-3254293-T-C is Benign according to our data. Variant chr16-3254293-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97545.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, not_provided=1, Benign=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.775A>G	p.Ile259Val	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+2018A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.775A>G	p.Ile259Val	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251446 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727248

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: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:4 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the MEFV protein (p.Ile259Val). This variant is present in population databases (rs104895144, gnomAD 0.006%). This missense change has been observed in individual(s) with however, in one of these individuals, a homozygous pathogenic allele was also identified in MEFV, which suggests this c.775A>G variant was not the primary cause of disease and/or Mediterranean fever (PMID: 22614345, 24469716, 25626331, 31989427). ClinVar contains an entry for this variant (Variation ID: 97545). 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 valine 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. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 14, 2018

The MEFV c.775A>G; p.Ile259Val variant (rs104895144), is reported in the literature in the heterozygous state in individuals affected with familial mediterranean fever (Ceylan 2012, Oztuzcu 2014, Tzifi 2014). This variant is reported in ClinVar (Variation ID: 97545), and is found in the general population with an overall allele frequency of 0.0032% (8/251,446 alleles) in the Genome Aggregation Database. The isoleucine at codon 259 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ile259Val variant is uncertain at this time. References: 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. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. Tzifi F et al. Acute hepatitis in a child heterozygous for the I259V MEFV gene variant. Prague Med Rep. 2014;115(3-4):128-33. -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 18, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 22, 2016

Variant summary: The variant c.775A>G (p.Ile259Val) affects a non-conserved nucleotide and results in replacement of Valine with an Isoleucine. Both amino acids are medium size and hydrophobic and therefore this substitution likely does not change the physico-chemical property of the protein. 5/5 in silico tools predict benign outcome for this change. The variant was found in the large and broad cohorts of the NHLBI-ES and ExAC projects at an allele frequency of 0.0025% which does not exceed the maximal expected allele frequency for a disease-causing MEFV variant (2.17%). However, the possibility that this variant may still represent as a rare polymorphism cannot be ruled out. There are a few patients with symptoms of FMF reported in the literature who carried the variant; however, most of these patient reports lack detailed clinical phenotypic data. Importantly, one patient with symptoms of FMF also carried p. M694V in homozygous state, indicating this variant may not be pathogenic or it acts as modifier of the pathogenic variant p.M694V. The variant p.M694V is known to be a highly penetrant pathogenic variant. Deletion of p.M694 has been shown to be causal for dominant FMF which also highlights the importance of p.M694 residue. There are no in vivo/vitro studies to describe the functional impact of the variant till date. Infevers database lists variant in one Turkish patient with a classification of VUS (unknown consequence) and HGMD lists variant with a classification of "Disease-Mutation". In summary, collective evidence suggests that this variant is unlikely to be pathogenic and it was classified as a VUS-possibly benign until more information becomes available. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 30, 2021

- -

MEFV-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

The MEFV c.775A>G variant is predicted to result in the amino acid substitution p.Ile259Val. This variant has been reported in five patients with familial Mediterranean fever (FMF), although segregation data was not presented in any of these cases and one patient was also homozygous for a different pathogenic variant (Ceylan et al. 2012. PubMed ID: 22614345; Oztuzcu et al. 2014. PubMed ID: 24469716; Tzifi et al. 2014. PubMed ID: 25626331; Balta et al. 2020. PubMed ID: 31989427). This variant was also reported in a patient with early coronary heart disease (Basar et al. 2014. PubMed ID: 24702757). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3304293-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Acute febrile neutrophilic dermatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	1.1
Dann	Benign	0.14
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.40	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.64
MutPred		0.71		Gain of helix (P = 0.005);
MVP		0.49
MPC		0.095
ClinPred		0.026	T
GERP RS		-2.1
Varity_R		0.022
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104895144; hg19: chr16-3304293;