chr16-3247166-G-C

Position:

chr16-3247166-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15U:3O:1

Conservation

PhyloP100: -0.0880

Variant links:

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]

MEFV links:

MEFV (HGNC:):

MEFV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=3, not_provided=1, Pathogenic=5, Likely_pathogenic=5}. Variant chr16-3247166-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.1437C>G	p.Phe479Leu	missense_variant	5/10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 linkuse as main transcript	c.804C>G	p.Phe268Leu	missense_variant	4/9		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.1437C>G	p.Phe479Leu	missense_variant	5/10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

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:

AN:

251496

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135922

show subpopulations

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:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727246

show subpopulations

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:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

show subpopulations

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.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:5Uncertain:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 02, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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 -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 11, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MEFV: PM3:Very Strong, PM2, BP4 -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 26, 2024

- -

Autoinflammatory syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 03, 2021

- -

Familial Mediterranean fever, autosomal dominant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Immunology and Genetics Kaiserslautern

Aug 27, 2024

ACMG Criteria: PS4, PM3, PM2_P, PP5; Variant was found in heterozygous state -

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

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

LIST_S2

Benign

0.59

T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.5

N;.;.;.

PrimateAI

Benign

0.26

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over