rs104895151

Positions:

• chr16-3247233-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000219596.6(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. 16/21 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 ENST00000219596.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1 O:1
• Conservation: PhyloP100: -1.51

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036343336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1370C>T	p.Ala457Val	missense_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.737C>T	p.Ala246Val	missense_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1370C>T	p.Ala457Val	missense_variant	5/10	1	NM_000243.3	ENSP00000219596	P3

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

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251348 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135864

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000397

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

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00806

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: 0.000526 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:8 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 06, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2023	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 supports 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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 14, 2019

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 20, 2020

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;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
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

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

Other links and lift over

dbSNP: rs104895151; hg19: chr16-3297233;