rs104895179

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000243.3(MEFV):​c.586G>T​(p.Gly196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,587,236 control chromosomes in the GnomAD database, including 17 homozygotes. 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. G196R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 6 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 11 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6O:1

Conservation

PhyloP100: -0.403
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0047331452).
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000541 (776/1434888) while in subpopulation AFR AF = 0.0188 (616/32682). AF 95% confidence interval is 0.0176. There are 11 homozygotes in GnomAdExome4. There are 328 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 6 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEFVNM_000243.3 linkc.586G>T p.Gly196Trp missense_variant Exon 2 of 10 ENST00000219596.6 NP_000234.1 O15553-2
MEFVNM_001198536.2 linkc.277+1829G>T intron_variant Intron 1 of 8 NP_001185465.2 O15553-3D2DTW2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEFVENST00000219596.6 linkc.586G>T p.Gly196Trp missense_variant Exon 2 of 10 1 NM_000243.3 ENSP00000219596.1 O15553-2

Frequencies

GnomAD3 genomes
AF:
0.00444
AC:
676
AN:
152232
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0151
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00222
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000470
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.00122
AC:
248
AN:
203408
AF XY:
0.000848
show subpopulations
Gnomad AFR exome
AF:
0.0189
Gnomad AMR exome
AF:
0.000611
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000485
Gnomad NFE exome
AF:
0.0000457
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000541
AC:
776
AN:
1434888
Hom.:
11
Cov.:
37
AF XY:
0.000460
AC XY:
328
AN XY:
712366
show subpopulations
Gnomad4 AFR exome
AF:
0.0188
AC:
616
AN:
32682
Gnomad4 AMR exome
AF:
0.000987
AC:
40
AN:
40540
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
25498
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39224
Gnomad4 SAS exome
AF:
0.0000706
AC:
6
AN:
84960
Gnomad4 FIN exome
AF:
0.000550
AC:
26
AN:
47238
Gnomad4 NFE exome
AF:
0.0000182
AC:
20
AN:
1100798
Gnomad4 Remaining exome
AF:
0.00105
AC:
62
AN:
59148
Heterozygous variant carriers
0
47
94
140
187
234
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
24
48
72
96
120
<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:
0.00444
AC:
676
AN:
152348
Hom.:
6
Cov.:
33
AF XY:
0.00417
AC XY:
311
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.0151
AC:
0.0150765
AN:
0.0150765
Gnomad4 AMR
AF:
0.00222
AC:
0.00222077
AN:
0.00222077
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.000470
AC:
0.000470455
AN:
0.000470455
Gnomad4 NFE
AF:
0.0000735
AC:
0.0000735143
AN:
0.0000735143
Gnomad4 OTH
AF:
0.00236
AC:
0.00236295
AN:
0.00236295
Heterozygous variant carriers
0
34
68
103
137
171
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00165
Hom.:
0
Bravo
AF:
0.00550
ESP6500AA
AF:
0.00960
AC:
38
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00138
AC:
158
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial Mediterranean fever Benign:4Other:1
-
Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Aug 22, 2023
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 06, 2020
Natera, Inc.
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 22, 2024
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:2Benign:1
Jul 20, 2016
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: The MEFV variant, c.586G>T (p.Gly196Trp), causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.20%, predominantly observed in the African subpopulation at a frequency of 2.4%. This frequency slightly exceeds the maximal expected allele frequency for a pathogenic variant in MEFV (2.2%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in at least 2 FMF patients, one of whom also had a common pathogenic mutation in the homozygous state (c.2082G>A, M694I; Gunesacar_2014), suggesting the variant of interest was not the causitive mutation in this individual. The variant has also been reported in atypical FMF patients and a Systemic Juvenile Idiopathic Arthritis patient, however the variant was the only detected variant in these patients. In addition, one reputable clinical lab has classified the variant as "benign", without evidence to independently evaluate. Taken together, this variant has been classified as a variant of uncertain significance, possibly benign variant, until additional information becomes available. -

Oct 21, 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.586G>T; p.Gly196Trp variant (rs104895179) is reported in the literature in several individuals with periodic fever or autoimmune syndromes (Bozgeyik 2020, Cantarini 2012, Oztuzcu 2014 ). However, the variant has also been reported in at least one individual with an alternate molecular explanation for disease (Gunesacar 2014). The variant is reported in the ClinVar database (Variation ID: 97532) and in the African population with an allele frequency of 1.7% (350/20,178 alleles including 2 homozygotes) in the Genome Aggregation Database. The glycine at codon 196 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.237). Although the allele frequency of this variant is higher than would be predicted for FMF, given the lack of clinical and functional data, the significance of the p.Gly196Trp variant is uncertain at this time. References: Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. PMID: 32199921. Cantarini L et al. Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene. Rheumatol Int. 2012 Feb;32(2):465-7. 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 Aug 10;546(2):195-9 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. -

Jul 03, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29178647, 26990548, 22995991, 20044784, 24929125, 24263150, 32199921) -

Familial Mediterranean fever, autosomal dominant Uncertain:1
Jul 23, 2020
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autoinflammatory syndrome Uncertain:1
May 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MEFV-related disorder Uncertain:1
May 14, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The MEFV c.586G>T variant is predicted to result in the amino acid substitution p.Gly196Trp. This variant has been reported in patients with Familial Mediterranean Fever (Jesus et al. 2012. PubMed ID: 22566169; Aydogan et al. 2013. PubMed ID: 23155201; Oztuzcu et al. 2014. PubMed ID: 24469716; Gunesacar et al. 2014. PubMed ID: 24929125; Bozgeyik et al. 2020. PubMed ID: 32199921) and systemic juvenile idiopathic arthritis (Cantarini et al. 2012. PubMed ID: 20044784). This variant is reported in 1.7% of alleles in individuals of African descent in gnomAD, including two homozygous individuals, which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1
Apr 03, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
14
DANN
Benign
0.79
DEOGEN2
Benign
0.35
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.47
T
MetaRNN
Benign
0.0047
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.24
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.46
P
Vest4
0.74
MVP
0.33
MPC
0.16
ClinPred
0.014
T
GERP RS
-2.3
Varity_R
0.070
gMVP
0.26
Mutation Taster
=65/35
polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104895179; hg19: chr16-3304482; API