rs104895076

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PM5PP3_ModerateBP6

The NM_000243.3(MEFV):c.443A>T(p.Glu148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,604,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E148Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:3O:1

Conservation

PhyloP100: 1.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3254626-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

BP6

Variant 16-3254625-T-A is Benign according to our data. Variant chr16-3254625-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2554.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=1, Uncertain_significance=8, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.443A>T	p.Glu148Val	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2 linkuse as main transcript	c.277+1686A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.443A>T	p.Glu148Val	missense_variant	2/10	1	NM_000243.3	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

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:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000768

AC:

AN:

234246

Hom.:

AF XY:

0.000100

AC XY:

AN XY:

129380

show subpopulations

Gnomad AFR exome

AF:

0.0000708

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000413

AC:

AN:

1452652

Hom.:

Cov.:

AF XY:

0.0000512

AC XY:

AN XY:

722468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000395

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000506

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000752

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:1Uncertain:2Benign:1Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 148 of the MEFV protein (p.Glu148Val). This variant is present in population databases (rs104895076, gnomAD 0.04%). This missense change has been observed in individual(s) with familial mediterranean fever (PMID: 17489852, 24469716, 28211254, 28483595, 29735907). ClinVar contains an entry for this variant (Variation ID: 2554). 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: "Deleterious"; PolyPhen-2: "Probably 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2015	The E148V variant of unknown significance has been previously published in association with familial Mediterranean fever and juvenile idopathic arthritis (Sever et al., 2012; Comak et al., 2013). It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E148V is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to glutamic acid are tolerated across species. However, in-silico analysis predicts this variant is probably damaging to the protein structure/function. Missense pathogenic variants at the same codon (E148Q) and in nearby residues (S141I, R143P) have also been reported in the Human Gene Pathogenic variant Database in association with familial Mediterranean fever (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2018	The MEFV c.443A>T; p.Glu148Val variant (rs104895076), is reported in the literature in the heterozygous, compound heterozygous, and homozygous state in individuals with a variety of symptoms, ranging from no symptoms to juvenile idiopathic arthritis to familial Mediterranean fever (Comak 2013, Dogan 2013, Dogan 2015, Giaglis 2007, Medlej-Hashim 2002, Sandhya 2017). This variant is reported in ClinVar (Variation ID: 2554), and is found in the South Asian population with an allele frequency of 0.043% (13/30,272 alleles) in the Genome Aggregation Database. The glutamic acid at codon 148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to conflicting phenotype information, the clinical significance of the p.Glu148Val variant is uncertain at this time. References: Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Dogan CS et al. Prevalence and significance of the MEFV gene mutations in childhood Henoch-Schonlein purpura without FMF symptoms. Rheumatol Int. 2013 Feb;33(2):377-80. Dogan H et al. Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. Gene. 2015 Sep 1;568(2):170-5. Giaglis S et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67. Medlej-Hashim M et al. Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. Clin Genet. 2002 Jan;61(1):71-3. Sandhya P et al. Egyptian tale from India: application of whole-exome sequencing in diagnosis of atypical familial Mediterranean fever. Int J Rheum Dis. 2017 Nov;20(11):1770-1775. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2022	Variant summary: MEFV c.443A>T (p.Glu148Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A recently reported in-silico ensemble method for predicting pathogenicity of missense variants (Rare Exome Variant Ensemble Learner, REVEL) predicted a computed classification for this variant as likely pathogenic (Accetturo_2020). The variant allele was found at a frequency of 7.7e-05 in 235044 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (7.7e-05 vs 0.022), allowing no conclusion about variant significance. Following a comprehensive and conservative assessment of literature spanning over thirteen years (2007-2020), c.443A>T, has been reported in the literature in a homozygous/compound heterozygous genotype in multiple individuals affected with Familial Mediterranean Fever (example, Giaglis_2007, Ibrahim_2015, Lachmann_2006, Cekin_2017, Sandhya_2017, Gumus_2018, Bozgeyik_2020, Tanatar_2020). Numerous publications also reported affected individuals lacking a second allele. In addition, the variant has also been reported in asymptomatic individuals. At-least one co-occurrence in cis with another pathogenic MEFV variant (p.M694V Tchernitchko 2003) has been ascertained in the context of this evaluation. Variable reports of the extent of genotyping and lack of clearly defined phase information (i.e., presumed trans versus cis co-occurrence) confound an accurate assessment from the ascertained literature. These data indicate that the variant may be associated with disease in some genetic backgrounds. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluations after 2014) cite the variant as "uncertain significance." Some submitters cite overlapping evidence utilized in the context of this evaluation. Therefore, due to the conflicting evidence outlined above, the variant has been classified as VUS-possibly pathogenic. -

Familial Mediterranean fever, autosomal dominant

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2023	- -

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

Apr 28, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2021

- -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2017

- -

Acute febrile neutrophilic dermatosis

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

0.18

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.17

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.071

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.83

MutPred

0.72

Loss of solvent accessibility (P = 0.0146);

MVP

0.88

MPC

0.58

ClinPred

0.26

GERP RS

4.4

Varity_R

0.28

gMVP

0.65

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