rs104895151

Variant names:

• chr16-3247233-G-A
• rs104895151
• NM_000243.3:c.1370C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000243.3(MEFV):​c.1370C>T​(p.Ala457Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,008 control chromosomes in the GnomAD database, including 1 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). Synonymous variant affecting the same amino acid position (i.e. A457A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1 O:1
• Conservation: PhyloP100: -1.51
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036343336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1370C>T	p.Ala457Val	missense_variant	Exon 5 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.737C>T	p.Ala246Val	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	c.1370C>T	p.Ala457Val	missense_variant	Exon 5 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000271 AC: 68 AN: 251348 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000148 AC: 217 AN: 1461824 Hom.: 1 Cov.: 33 AF XY: 0.000142 AC XY: 103 AN XY: 727220

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112008

Other (OTH) AF: 0.000397 AC: 24 AN: 60392

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000418 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:2 Benign:1 Other:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:3

Jul 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as heterozygous in an individual with fibromyalgia syndrome and an unrelated individual with FMF and small fiber neuropathy; both individuals were also heterozygous for the E148Q, P369S and R408Q variants, with all 4 variants on the same allele (in cis) (PMID: 20041150, 32133669); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27332769, 29579081, 32133669, 34426522, 32806879, 20041150, 29599418, 29927949, 30476936, 25203624) -

Jun 06, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.1370C>T; p.Ala457Val variant (rs104895151) has been reported in an individual with periodic fever syndrome (Infevers database), and another individual with fibromyalgia syndrome (Feng 2009). However, in the latter case, the variant was paternally inherited, and found in-cis with p.Glu148Gln, p.Pro369Ser and p.Arg408Gln, with no variants detected on the maternal chromosome (Feng 2009). The variant is listed in ClinVar (Variation ID: 97441), and observed in the general population at an overall frequency of 0.03% (73/277128 alleles) in the Genome Aggregation Database. The alanine at residue 457 is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Infevers database: http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n=1 Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009;4(12):e8480. -

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:2

Mar 30, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV NM_000243.2 exon 5 p.Ala457Val (c.1370C>T): This variant has been reported in the literature in at least 2 individuals with features of Familial Mediterranean Fever (FMF). This variant is often reported in cis with several other variants (p.Glu148Gln, p.Pro369Ser, p.Arg408Gln) as part of a complex heterozygote; however at least 1 individual was reported to have this variant in trans (Lainka 2012 PMID:22903357, Mneimneh 2016 PMID:n/a). Of note, this variant was also found in cis with the same variants in 1 patient with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.5% (54/10368) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3297233-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97441) and the infevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). This variant amino acid Valine (Val) is present in 9 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

May 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Uncertain:1

Jun 14, 2019

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.1370C>T (p.Ala457Val) 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 0.00028 in 252058 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00028 vs 0.022), allowing no conclusion about variant significance. c.1370C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever (Lainka_2012, Mneimneh_2016). It was also reported in one heterozygous patient presented with Fibromyalgia Syndrome who had inherited the variant from his apparently unaffected heterozygous father (Fen_2009). These reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Recently, the International Study Group for Systemic Autoinflammatory Diseases (INSIAD) involving experts on hereditary recurrent fever genetics, provided a classification of likely benign with a provisional status for c.1370C>T (Van Gijn_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of functional or clinical significance become available. -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Mar 20, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV NM_000243.2 exon 5 p.Ala457Val (c.1370C>T): This variant has been reported in the literature in at least 2 individuals with features of Familial Mediterranean Fever (FMF). This variant is often reported in cis with several other variants (p.Glu148Gln, p.Pro369Ser, p.Arg408Gln) as part of a complex heterozygote; however at least 1 individual was reported to have this variant in trans (Lainka 2012 PMID:22903357, Mneimneh 2016 PMID:n/a). Of note, this variant was also found in cis with the same variants in 1 patient with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.5% (54/10368) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3297233-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97441) and the infevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). This variant amino acid Valine (Val) is present in 9 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.26
DANN	Benign	0.49
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.26	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;.;.;.
PhyloP100		-1.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.050	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.068	T;T;T;T
Sift4G	Uncertain	0.030	D;D;T;D
Polyphen		0.0	B;.;.;.
Vest4		0.056
MVP		0.49
MPC		0.11
ClinPred		0.012	T
GERP RS		-4.4
Varity_R		0.052
gMVP		0.075
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs104895151; hg19: chr16-3297233;