16-3243593-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_000243.3(MEFV):c.1894G>A(p.Gly632Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,602,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G632A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:10O:1

Conservation

PhyloP100: 0.248

Publications

14 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: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 16-3243593-C-T is Pathogenic according to our data. Variant chr16-3243593-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97467.

BP4

Computational evidence support a benign effect (MetaRNN=0.05887896). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.1894G>A	p.Gly632Ser	missense_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 link	c.*98G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.1894G>A	p.Gly632Ser	missense_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

243550

AF XY:

0.0000380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000542

Gnomad OTH exome

AF:

0.000513

GnomAD4 exome

AF:

0.0000345

AC:

AN:

1450042

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

720144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33050

American (AMR)

AF:

0.0000230

AC:

AN:

43460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53040

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000371

AC:

AN:

1105056

Other (OTH)

AF:

0.0000335

AC:

AN:

59778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

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:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000859

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:1Uncertain:4Other:1

Jul 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 632 of the MEFV protein (p.Gly632Ser). This variant is present in population databases (rs104895128, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive MEFV-related conditions (PMID: 16730661, 17938136, 24469716, 25286988, 27310525, 27473114). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97467). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 22, 2016

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MEFV c.1894G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Ser. One structual study predicted this variant to be stabilizing (Arakelov_2015) and 3/4 in-silico tools predict this variant to be benign; however, functional studies have not been carried out to confirm these findings and in silico predictions are known to have low sensitivity and specificity for immunological gene variants. This variant is found in 5/122392 control chromosomes at a frequency of 0.0000409, which does not exceed the maximal expected frequency of a pathogenic allele (0.0216506) in this gene. No homozygotes have been reported in general population. The variant has been reported in at least eight FMF patients, one known to be compound heterozygous for a known pathogenic variant and three were homozygous for the variant. One family reported by Shinar_2007 also showed an indication that this variant cosegregated with disease. These patient data strongly suggests for a pathogenic outcome. This variant was also found in patients with adult-onset Stills disease and Behcet disease. The variant is considered a mild pathogenic mutation (Shinar_2007). Taken together, this variant has currently been classified as a Likely Pathogenic. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2019

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is predicted to replace glycine with serine at codon 632 of the MEFV protein (p.(Gly632Ser)). The glycine residue is not conserved (100 vertebrates, UCSC), and is located in the B30.2/SPRY domain. There is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with a recessive condition (10/274,946 alleles, 0 homozygotes in gnomAD v2.1). It has been identified heterozygous (alone), homozygous, and with a second MEFV allele in multiple cases with familial Mediterranean fever (FMF), and has been reported to segregate with disease dominantly in a single family with incomplete penetrance PMID: 17938136, 23137073, 24469716, 27310525). Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Another missense variant at this position (p.(Gly632Ala)) has been identified in Turkish FMF cases (PMID: 23862117, 33738724). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3_Strong, PM2_Supporting, BP4. -

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

Pathogenic:1Uncertain: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 10 p.Gly632Ser (c.1894G>A): This variant has been reported in the literature in the heterozygous and compound heterozygous state in at least 3 individuals with Familial Mediterranean Fever (FMF), potentially segregating with disease in at least 2 affected family members (Shinar 2007 PMID:17938136). This variant has also been reported in at least 1 individual with adult onset Still's disease (Nonaka 2015 PMID:25286988, Umeda 2017 PMID:27310525). This variant is present in 0.001% (1/68022) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243593-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:97467). This variant amino acid Serine (Ser) is present in >20 species including mammals 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. -

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Pathogenic:1Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 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

Familial Mediterranean fever, autosomal dominant

Uncertain:2

Mar 23, 2023

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEFV c.1894G>A variant is classified as a VUS (PS4_Supporting, PM2, PM3) The MEFV c.1894G>A variant is a single nucleotide change in exon 10/10 of the MEFV gene, which is predicted to change the amino acid glycine at position 632 in the protein to serine. The variant has been reported in patients with familial mediterranean fever, as heterozygous, compound heterozygous and homozygous (PMID:17938136, PMID:23137073, PMID:24469716) (PS4_Supporting, PM3). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0014%, Non-Finnish European population) (PM2). The variant has been reported in dbSNP (rs104895128) and as disease causing in the HGMD database (CM0045304). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 97467). Another missense variant at the same amino acid location, p.Gly632Ala, has been reported on the HGMD database as disease causing (CM146757). -

Feb 14, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 16, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEFV c.1894G>A; p.Gly632Ser variant (rs104895128) is reported in the literature in multiple individuals affected with familial Mediterranean fever (Goulielmos 2006, Oztuzcu 2014, Shinar 2007, Umeda 2017) and in an individual with adult-onset Still’s disease (Nonaka 2015). This variant is also reported in ClinVar (Variation ID: 97467). This variant is found in the general population with an overall allele frequency of 0.004% (10/274946 alleles) in the Genome Aggregation Database. The glycine at codon 632 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.255). Due to limited information, the clinical significance of the p.Gly632Ser variant is uncertain at this time. References: Goulielmos GN et al. Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF). Biochem Biophys Res Commun. 2006 Jul 14;345(4):1326-32. PMID: 16730661. 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. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. PMID: 24469716. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. PMID: 17938136. Umeda M et al. A Japanese familial Mediterranean fever patient with a rare G632S MEFV mutation in exon 10. Mod Rheumatol. 2017 Mar;27(2):378-379. PMID: 27310525. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.41

CADD

Benign

1.2

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.20

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.28

N;.;.

PhyloP100

0.25

PrimateAI

Benign

0.23

PROVEAN

Benign

0.99

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.012

B;.;.

Vest4

0.094

MVP

0.26

MPC

0.12

ClinPred

0.030

GERP RS

-2.4

Varity_R

0.35

gMVP

0.22

Mutation Taster

=20/80

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over