rs104895100

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000243.3(MEFV):c.1459G>C(p.Val487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,614,190 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. V487M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: -0.245

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

familial Mediterranean fever
Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
autosomal recessive familial Mediterranean fever
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
familial Mediterranean fever, autosomal dominant
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MEFV links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031388104).

BP6

Variant 16-3247144-C-G is Benign according to our data. Variant chr16-3247144-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378132.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.1459G>C	p.Val487Leu	missense_variant	Exon 5 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 link	c.826G>C	p.Val276Leu	missense_variant	Exon 4 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.1459G>C	p.Val487Leu	missense_variant	Exon 5 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00784

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000612

AC:

154

AN:

251496

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000217

AC:

317

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00732

AC:

245

AN:

33480

American (AMR)

AF:

0.000716

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112000

Other (OTH)

AF:

0.000447

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00224

AC:

341

AN:

152314

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00786

AC:

327

AN:

41580

American (AMR)

AF:

0.000720

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.00267

ESP6500AA

AF:

0.00797

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEFV c.1459G>C; p.Val487Leu variant (rs104895100) has been reported in individuals affected with familial Mediterranean fever (see link to database, Gumus 2018, Moradian 2017), but was not determined to be causative and was classified as "unsolved" by an expert panel (Van Gijn 2018). The variant is reported in the ClinVar database (Variation ID: 378132) and is reported in the African population with an allele frequency of 0.76% (189/24,964 alleles including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.075). Although the population frequency of this variant is relatively high, the possibility of reduced penetrance or a mild effect cannot be excluded. Therefore, due to conflicting information and lack of functional data, the significance of this variant cannot be determined with certainty. References: Link to Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 Gumus E. The Frequency of MEFV Gene Mutations and Genotypes in Sanliurfa Province, South-Eastern Region of Turkey, after the Syrian Civil War by Using Next Generation Sequencing and Report of a Novel Exon 4 Mutation (I423T). J Clin Med. 2018 May 7;7(5):105. PMID: 29735907. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537. PMID: 29599418. -

Nov 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Familial Mediterranean fever

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This MEFV missense variant has been reported in an individual suspected to have familial Mediterranean fever. The variant (rs104895100) is present in a large population dataset (gnomAD v3.1.2: 339/152196 total alleles; 0.223%; 3 homozygotes), and has been reported in ClinVar2 (Variation ID 378132). Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The valine residue at this position is evolutionarily conserved across very few of the species assessed, and most of the species have leucine at this position. We consider the clinical significance of c.1459G>C; p.Val487Leu in MEFV to be uncertain at this time. -

not specified

Uncertain:1

Apr 19, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MEFV c.1459G>C (p.Val487Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251496 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00061 vs 0.022), allowing no conclusion about variant significance. c.1459G>C has been reported in the literature in an individual (heterozygous) with clinically suspected Familial Mediterranean Fever (Gumus_2018). In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported classification and status of this variant as Unsolved (Van Gijn_2018). Recently however, Accetturo et al proposed a classification of likely benign (Accetturo _2019) based on a variant metapredictor tool REVEL (Rare Exome Variant Ensemble Learner) for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31411330, 29599418, 29735907, 29178647). ClinVar contains an entry for this variant (Variation ID: 378132). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Familial Mediterranean fever, autosomal dominant

Uncertain:1

Feb 27, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Benign:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.35

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.27

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.5

N;.;.;.

PhyloP100

-0.24

PrimateAI

Benign

0.25

PROVEAN

Benign

1.5

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.051

MutPred

0.46

Loss of MoRF binding (P = 0.336);.;.;.;

MVP

0.38

MPC

0.11

ClinPred

0.0087

GERP RS

2.3

Varity_R

0.11

gMVP

0.12

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over