rs75977701

Positions:

chr16-3254158-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP6BS1BS2_Supporting

The NM_000243.3(MEFV):c.910G>A(p.Gly304Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,990 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 32 hom. )

Consequence

MEFV
NM_000243.3 missense, splice_region

Scores

Splicing: ADA: 0.9978

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6O:1

Conservation

PhyloP100: 0.0780

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 Likely_benign. Variant got -5 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 16-3254158-C-T is Benign according to our data. Variant chr16-3254158-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36513.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=2, Uncertain_significance=5}. Variant chr16-3254158-C-T is described in Lovd as [Likely_benign]. Variant chr16-3254158-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0034 (518/152332) while in subpopulation EAS AF= 0.0224 (116/5180). AF 95% confidence interval is 0.0191. There are 3 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 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/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.910G>A	p.Gly304Arg	missense_variant, splice_region_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.277+2153G>A		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.910G>A	p.Gly304Arg	missense_variant, splice_region_variant	2/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.00340

AC:

518

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00458

AC:

1144

AN:

249962

Hom.:

AF XY:

0.00430

AC XY:

582

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.0180

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.000934

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00209

AC:

3058

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1534

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.0222

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.0263

Gnomad4 NFE exome

AF:

0.000289

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.00340

AC:

518

AN:

152332

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

338

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0224

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00138

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MEFV p.Gly304Arg variant has been reported many times in the literature in relation multiple phenotypes, mainly familial Mediterranean fever (FMF) or phenotypes involving reoccuring fevers, as well as rheumatic disease and other autoimmune phenotypes, however the variant has also been reported to a large extent in healthy control populations (Ebrahimi-Fakhari_2012_PMID: 23137073; Arasawa_2012_PMID: 23217869; Migita_2013_PMID: 23437051; Gunesacar_2014_PMID: 24929125; Yoshioka_2014_PMID: 25088882; Migita_2014_PMID: 24261781; Comak_2014_PMID: 23588594; Fujikawa_2014_PMID: 24965843; Jo_2015_PMID: 25671271; Moritake_2016_ PMID: 26933204; Nonaka_2015_PMID: 25286988; Taniuchi_2013_PMID: 23847694). The variant was identified in 11/384 alleles (freq=0.029) from patients with sure or probable FMF, 19/818 alleles (freq=0.023) from patients with unexplained fever but with an unlikely diagnosis of FMF and in 6/210 alleles (freq=0.029) from healthy controls (Migita_2016_PMID: 27473114). Another study identified the G304R variant in 2/116 patients with FMF as a complex compound heterozygous allele as these patients each carried two other MEFV variants (Kishida_2014_ PMID: 25261100). A study that performed mutational analysis of the MEFV gene on a patient with periodic fever and chest pain who was suspected to have FMF identified the G304R variant only in the patient's healthy mother and sister but not in the affected patient (Oshima_2009_19967574). However, a functional study identified two cases of FMF that were homozygous for the G304R variant and found that the variant caused excessive exon 2 skipping due to alternative splicing in these patients, suggesting that this abberant splicing was causal of thier phenotype. Transfection of wild-type andÂ¬â€ Â¬â€ G304R variant MEFV constructs into HEK293T cells resulted in aberrant splicing of the mutant construct leading to abnormal protein size, presumably causing loss of pyrin function (Tone_2012_ PMID: 21562927). This p.G304R was also identified in dbSNP (ID: rs75977701), ClinVar (classified as benign by Invitae, likely benign by Counsyl, likely pathogenic by GeneDx and as a VUS by ARUP Laboratories and Integrated Genetics), Cosmic (FATHMM prediction of neutral; score=0.00) and LOVD 3.0. The variant was identified in control databases in 1318 of 281346 chromosomes (12 homozygous) at a frequency of 0.004685 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 686 of 25046 chromosomes (freq: 0.02739), East Asian in 360 of 19930 chromosomes (freq: 0.01806), Other in 46 of 7206 chromosomes (freq: 0.006384), Ashkenazi Jewish in 43 of 10360 chromosomes (freq: 0.004151), South Asian in 33 of 30606 chromosomes (freq: 0.001078), European (non-Finnish) in 130 of 127858 chromosomes (freq: 0.001017) and African in 20 of 24910 chromosomes (freq: 0.000803); it was not observed in the Latino population. The p.Gly304Arg variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Further,Â¬â€ Â¬â€ 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of the 5' splice site. The functional study by Tone et al. described above also confirmed this abberant splicing prediction (Tone_2012_ PMID: 21562927). However, the p.Gly304 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain signi -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Reported in the presence of other MEFV variants in individuals with familial Mediterranean fever or unexplained fevers in published literature; however, many of these variants are of uncertain clinical significance (Migita et al., 2012; Kishida et al., 2014); Published functional studies suggest that variant alters gene splicing with skipping of exon 2, while the functional consequences of the resulting truncated protein product remain unknown and loss-of-function is not an established mechanism of disease (Tone et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cis with a pathogenic MEFV variant in at least one family referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 28943464, 28863210, 32398039, 31401792, 23847694, 26933204, 23437051, 24965843, 24261781, 25525159, 21562927, 25671271, 24929125, 19967574, 23588594, 25261100, 23217869, 25286988, 25088882, 22467954, 25703702, 23137073, 30235678, 31155445, 31494649, 31682063, 32082075, 29178647, 31998953, 31989427, 31803701, 32824452, 31342094, 32115236, 33974187, Sargin[case report], 34177904, Tomokawa[other], 33733382, 34904166) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 20, 2023	The MEFV c.910G>A; p.Gly304Arg variant (rs75977701) is reported in the literature in individuals affected with atypical familial Mediterranean fever (Arasawa 2012, Gunesacar 2014, Kishida 2014, Migita 2014), but also in healthy controls (Migita 2012, Nonaka 2015, Oshima 2010, Taniuchi 2013). This variant is reported with conflicting interpretations of pathogenicity in ClinVar (Variation ID: 36513), and is found in the general population with an overall allele frequency of 0.47% (1318/281346 alleles, including 12 homozygotes), with an increased frequency in the Finnish European population of 2.7% (686/25046 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.055). However, this variant resides in the last nucleotide of exon 2, and is predicted to disrupt the canonical splice donor site (Alamut v.2.11), with functional studies supporting a negative impact on gene function (Tone 2012). Due to conflicting information, the clinical significance of the p.Gly304Arg variant is uncertain at this time. References: Arasawa S et al. Mediterranean mimicker. Lancet. 2012 380(9858):2052. PMID: 23217869. Gunesacar R et al. Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene. 2014 546(2):195-9. PMID: 24929125. Kishida D et al. Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations. Arthritis Res Ther. 2014 16(5):439. PMID: 25261100. Migita K et al. Clinical relevance of MEFV gene mutations in Japanese patients with unexplained fever. J Rheumatol. 2012 Apr;39(4):875-7. PMID: 22467954. Migita K et al. Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol. 2014 24(1): 212-6. PMID: 24261781. Nonaka F et al. Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease. Clin Exp Immunol. 2015 Mar;179(3):392-7. PMID: 25286988. Oshima K et al. A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan. Mod Rheumatol. 2010 Apr;20(2):193-5. PMID: 19967574. Taniuchi S et al. MEFV Variants in Patients with PFAPA Syndrome in Japan. Open Rheumatol J. 2013 7:22-5. PMID: 23847694. Tone Y et al. Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever. Mod Rheumatol. 2012 22(1):45-51. PMID: 21562927. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MEFV: PP3, BS1, BS2 -

Familial Mediterranean fever

Uncertain:1Benign:2Other:1

Likely benign, criteria provided, single submitter	literature only	Counsyl	Dec 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2023	Variant summary: MEFV c.910G>A (p.Gly304Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant also alters a non-conserved nucleotide, positioned as the last nucleotide of exon 2 adjacent to the canonical splice donor site of intron 2. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. These predictions are supported by at least one publication which demonstrated that the variant increases the in-frame skipping of exon 2 in patients PBMCs, due to enhanced alternative splicing (Tone_2012). Authors transfected the normal and variant MEFV genes into HEK293T (embryonic kidney origin) cells, however the transfectants (i.e. both the full-length mutant containing the G304R missense change, and the exon 2 deleted short isoform) failed to show altered intracellular pyrin distribution in this cell type. As the cell system used by the authors may not represent a physiological cell type, the functional significance of this variant remains unclear at the cellular and/or organismal level. The variant allele was found at a frequency of 0.0046 in 250756 control chromosomes, predominantly at a frequency of 0.018 within the East Asian subpopulation in the gnomAD database, including 12 homozygotes. Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within some East Asian subpopulations (e.g. in Chinese Dai in Xishuangbanna (CDX) 5.4%, Han Chinese in Beijing (CHB) 2.4%, Japanese in Tokyo (JPT) 2.9%, Kinh in Ho Chi Minh City in Vietnam (KHV) 2.5%), suggesting this variant is likely a benign polymorphism (Moradian_2017). Though the variant, c.910G>A, has been reported in the literature in individuals affected with Familial Mediterranean Fever (FMF) (example, Arasawa_2012, Comak_2013, Coskun_2015, Ebrahmi-Fakhari_2012, Fujikawa_2014, Gunesacar_2014, Jo_2015, Kishida_2014, Migita_2012, Migita_2014, Migita_2013, Oshima_2010, Tone_2012, Yoshioka_2014, Migita_2016, Moritake_2016, Erdem_2017, Ebadi_2017, Hara_2018, Dundar_2022), a recent study evaluating the prevalence of the disease in the Japanese population (Migita_2016) found similar allele frequencies among FMF patients (2.9%; 11/384 alleles) and healthy subjects (2.9%; 6/210 alleles). This frequency among healthy Japanese controls is comparable to that reported in large Japanese control population databases (i.e. 2.6% in jMorp, and 2% in HGVD). A functional study analyzed the effects of certain MEFV variants on cell death with or without stimulation with Clostridium difficile toxin A (TcdA) or UCN-01A and concluded that p.Gly304Arg conferred no substantial increase in cell death (Honda_2021). Additionally, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of likely benign for the variant (Van Gijn_2018). One ClinVar submitter (evaluation after 2014) cites the variant as benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. At-least one submitter has re-classified this variant from a likely pathogenic to a VUS outcome since its previous evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

MEFV-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The MEFV c.910G>A variant is predicted to result in the amino acid substitution p.Gly304Arg. This variant has been reported in patients with familial mediterranean fever (Tone et al. 2012. PubMed ID: 21562927; Ebadi et al. 2017. PubMed ID: 28943464) and in a patient with Sweets syndrome, myelodyplastic syndrome, high fever and leukocytosis (Jo et al. 2015. PubMed ID: 25671271). The c.910G>A substitution resides near the consensus intron 2 splice donor site and is predicted to abolish this splice donor site (Alamut v.2.11). Biochemical analysis in one report indicates that the c.910G>A substitution causes aberrant exon splicing and results in a truncated MEFV protein (Tone et al. 2012. PubMed ID: 21562927). This variant is also reported at a maximum allele frequency of 1.7% in East Asians and 2.75% in the Finnish population and has been reported in several individuals in the homozygous state in databases of apparently unaffected individuals (http://gnomad.broadinstitute.org/variant/16-3304158-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00076

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

REVEL

Benign

0.055

Sift

Uncertain

0.0010

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.21

MutPred

0.24

Gain of solvent accessibility (P = 0.019);

MVP

0.51

MPC

0.14

ClinPred

0.0094

GERP RS

-1.4

Varity_R

0.16

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.71

Position offset: 0

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