rs11466045

Positions:

• chr16-3243880-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000243.3(MEFV):​c.1772T>C​(p.Ile591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,932 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.0099 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (186 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10 O:1
• Conservation: PhyloP100: -1.01

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 Benign. Variant got -11 ACMG points.

• PM1: In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.003907919).
• BP6: Variant 16-3243880-A-G is Benign according to our data. Variant chr16-3243880-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36506.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, not_provided=1, Uncertain_significance=3}. Variant chr16-3243880-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00985 (1500/152258) while in subpopulation NFE AF= 0.016 (1090/68018). AF 95% confidence interval is 0.0152. There are 17 homozygotes in gnomad4. There are 713 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1772T>C	p.Ile591Thr	missense_variant	9/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.1314T>C	p.Asp438=	synonymous_variant	8/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1772T>C	p.Ile591Thr	missense_variant	9/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1501 AN: 152140 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0107 AC: 2682 AN: 251076 Hom.: 21 AF XY: 0.0106 AC XY: 1441 AN XY: 135784

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.0150 AC: 21896 AN: 1461674 Hom.: 186 Cov.: 31 AF XY: 0.0144 AC XY: 10476 AN XY: 727102

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00457

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.00985 AC: 1500 AN: 152258 Hom.: 17 Cov.: 32 AF XY: 0.00958 AC XY: 713 AN XY: 74446

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0137 Hom.: 38

Bravo AF: 0.00876

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0152 AC: 131

ExAC AF: 0.0102 AC: 1240

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 25, 2018	Across a selection of available literature, the MEFV c.1772T>C (p.Ile591Thr) missense variant has been identified in a total of 17 patients with familial Mediterranean fever (FMF), including in a compound heterozygous state in five patients and in a heterozygous state in twelve patients (Touitou 2001; Aldea et al. 2002; Tchernitchko et al. 2005; Fisher et al. 2005; Cañete et al. 2007; Ustek et al. 2008; Cornelius et al. 2011; Ait-Idir et al. 2011; Ceylan et al. 2012; Hernández-Rodríguez et al. 2016). Additionally, Aldea et al. (2002) reported the p.Ile591Thr variant in one affected individual in a compound heterozygous state with another known pathogenic variant. However, two siblings who also carried both of the identified variants were asymptomatic, suggesting that the p.Ile591Thr variant may not be disease-causing. This variant was found in six of 1310 control chromosomes (Aldea et al. 2002; Cañete et al. 2007; Ustek et al. 2008; Ait-Idir et al. 2011) and is reported at a frequency of 0.02336 in the Toscani in Italia population of the 1000 Genomes Project. Additionally, twenty three homozygotes are present in the Genome Aggregation Database. Based on the combined evidence, this variant does not appear to be disease-causing in the same manner as known pathogenic FMF variants, but some of the studies suggest that this variant may be a risk allele, modifier or mild allele that displays low penetrance. The p.Ile591Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MEFV: PM5, BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30476289, 29239128, 28748511, 29735907, 28191008, 29047407, 28386255, 28236224, 27943240, 28624931, 28302131, 28631068, 29178647, 28194777, 28158814, 27535533, 21228398, 16255051, 11464238, 17665427, 26299986, 20041150, 22995991, 16100353, 20721559, 12124996) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2022	Variant summary: MEFV c.1772T>C (p.Ile591Thr) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The variant allele was found at a frequency of 0.011 in 285086 control chromosomes, including 24 homozygotes (gnomAD and publication data). It was predominantly found within the European Finnish and non-Finnish subpopulations at a frequency of 0.021 and 0.017, respectively. These frequencies are close to the maximum expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.022). Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within the British (0.022) and Toscani (Italian) (0.0234) subpopulation, suggesting this variant is likely a benign polymorphism found primarily in the populations of European origin. This variant has been mostly reported in heterozygous state in patients with Familial Mediterranean Fever (FMF), together with limited reports of compound heterozygosity in multiple ethnicities, without strong evidence for causality (e.g. Fisher 2005, Ait-Idir 2011, Lainka 2012, Papa 2017, Gumus 2018, Stella 2019). Additionally, in a Spanish family, the variant did not co-segregate with the disease, suggestive of an incomplete penetrance or a mostly benign impact (Aldea 2002). In a recent study the variant was found in heterozygous state in a cohort of FMF patients with a similar allele frequency (0.0113), as it was reported in controls in the gnomAD database (Balta_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and the Gene Reviews database have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1), VUS (n=4), likely benign (n=3) / benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Acute febrile neutrophilic dermatosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 06, 2018

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

The p.I591T variant (also known as c.1772T>C), located in coding exon 9 of the MEFV gene, results from a T to C substitution at nucleotide position 1772. The isoleucine at codon 591 is replaced by threonine, an amino acid with similar properties. This variant was reported in Spanish kindred in which the proband, a 25 year old male, exhibited recurrent fever accompanied by abdominal pain and synovitis; renal function was normal, no amyloid deposition was observed, and he was responsive to colchicine treatment. The p.I591T alteration was confirmed to be in trans (on the opposite chromosomes) with the p.M694I mutation; each of the his asymptomatic parents carried one alteration. In addition, his two siblings, ages 34 and 35, were also compound heterozygous for p.I591T and p.M694I but were asymptomatic (Aldea A et al. Hum Mutat. 2002;20:148-150). In a study of 71 unrelated patients with a clinical diagnosis of familial Mediterranean fever (FMF), one patient was found to carry both p.I591T alteration and the p.M694I mutation, however the phase (cis vs. trans) was not described (Ait-Idir D et al. Rheumatology (Oxford), 2011 Dec;50:2306-10). In a recent study of clinical and genetic features of adults with autoinflammatory disease, one patient with FMF was heterozygous for this alteration and a benign polymorphism in MEFV; a second patient, with a primary diagnosis of tumor necrosis factor-receptor associated periodic syndrome (TRAPS) was also heterozygous for p.I591T, was reported to have clinical overlap with FMF, and was responsive to colchicine treatment (Hernández-Rodríguez J et al. Autoimmun Rev, 2016 Jan;15:9-15). This variant was previously reported in the SNPDatabase as rs11466045. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.76% (16/2098) total alleles studied. The highest observed frequency was 3.57% (1/28) Spanish alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 1.08% (140/12994) total alleles studied, having been observed in 0.2% (9/4394) African American alleles and 1.52% (131/8600) European American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 21, 2022

MEFV NM_000243.2 exon9 p.Ile591Thr (c.1772T>C): This variant has been reported in the literature as a compound heterozygote in at least 2 individuals with Familial Mediterranean Fever (FMF) as well as a heterozygote in at least 5 individuals with FMF (Aldea 2002 PMID:12124996, Tchernitchko 2005 PMID:16255051, Ustek 2008 PMID:19026119, Toutou 2010 PMID:11464238, Ait-Idir 2011 PMID:22019805, Ceylan 2012 PMID:22614345). This variant is present in 2.1% (526/25104) of Finnish alleles, including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-3293880-A-G). This variant is present in ClinVar (Variation ID:36506). This variant amino acid Threonine (Thr) is present in >10 species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, despite the high minor allele frequency, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.10
DANN	Benign	0.32
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.47	T;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.17
MPC		0.15
ClinPred		0.00067	T
GERP RS		-7.4
Varity_R		0.067
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11466045; hg19: chr16-3293880; COSMIC: COSV99045951; COSMIC: COSV99045951;