chr16-3254739-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000243.3(MEFV):ā€‹c.329T>Cā€‹(p.Leu110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,772 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. L110L) has been classified as Benign.

Frequency

Genomes: š‘“ 0.0029 ( 15 hom., cov: 34)
Exomes š‘“: 0.0024 ( 121 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 0.501
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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0020012558).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEFVNM_000243.3 linkc.329T>C p.Leu110Pro missense_variant Exon 2 of 10 ENST00000219596.6 NP_000234.1 O15553-2
MEFVNM_001198536.2 linkc.277+1572T>C 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.329T>C p.Leu110Pro missense_variant Exon 2 of 10 1 NM_000243.3 ENSP00000219596.1 O15553-2

Frequencies

GnomAD3 genomes
AF:
0.00288
AC:
438
AN:
152170
Hom.:
15
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0797
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00657
AC:
1625
AN:
247318
Hom.:
61
AF XY:
0.00605
AC XY:
816
AN XY:
134804
show subpopulations
Gnomad AFR exome
AF:
0.0000651
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.000401
Gnomad EAS exome
AF:
0.0842
Gnomad SAS exome
AF:
0.00121
Gnomad FIN exome
AF:
0.0000466
Gnomad NFE exome
AF:
0.000144
Gnomad OTH exome
AF:
0.00214
GnomAD4 exome
AF:
0.00236
AC:
3448
AN:
1460482
Hom.:
121
Cov.:
64
AF XY:
0.00228
AC XY:
1656
AN XY:
726570
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000425
Gnomad4 ASJ exome
AF:
0.000344
Gnomad4 EAS exome
AF:
0.0753
Gnomad4 SAS exome
AF:
0.00118
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.000131
Gnomad4 OTH exome
AF:
0.00296
GnomAD4 genome
AF:
0.00287
AC:
437
AN:
152290
Hom.:
15
Cov.:
34
AF XY:
0.00309
AC XY:
230
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0797
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00295
Hom.:
21
Bravo
AF:
0.00313
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000778
AC:
3
ExAC
AF:
0.00620
AC:
750
Asia WGS
AF:
0.0170
AC:
58
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:2
Feb 28, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 03, 2019
GeneDx
Significance: 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; Reported in both the heterozygous and homozygous states in unaffected individuals and in individuals with familial Mediterranean fever (Kim et al., 2006; Tomiyama et al., 2008); This variant is associated with the following publications: (PMID: 24965843, 17329916, 22989844, 23166428, 24797171, 24598070, 10854105, 24929125, 20041150, 25073670, 22534884, 26332735, 29017770, 28482392, 29178647, 26537665, 19967574, 18328141, 25261100, 29642170, 26457478, 29526930, 29151129, 24661635, 32199921, 32735870) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 26, 2024
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial Mediterranean fever Uncertain:3Benign:1
May 18, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 07, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:1
May 02, 2022
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.329T>C (p.Leu110Pro) 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 allele was found at a frequency of 0.0066 in 247780 control chromosomes, predominantly at a frequency of 0.084 within the East Asian subpopulation in the gnomAD database, including 61 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever phenotype (0.022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, the variant c.329T>C has also been commonly reported in FMF patients, primarily in the same allele (in cis) with p.E148Q, both in heterozygote and homozygote phases. In addition, multiple publications show lack of cosegregation for the variant and disease (Oshima_2010, Berdeli_2011, and Kim_2007). In Japanese population, the variant's allele frequency is higher in patients than in controls. Case-control studies in Japanese population indicate this variant may associate with increased risk of FMF (OR= 1.78, Migita_2016; OR=4.81, Tsuchiya-Suzuki_2009). Larger case-control studies are needed to validate these findings. At least one functional study demonstrated no damaging effect of this variant (Honda_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of uncertain significance for the variant (Van Gijn_2018). Based on the data available at this time, it is unknown whether this variant represents a low penetrance mild common pathogenic variant, modifier, or a risk allele. Therefore, this variant was classified as uncertain significance, until additional information becomes available. -

Oct 14, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autoinflammatory syndrome Benign:1
May 03, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
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
0.054
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
12
DANN
Benign
0.88
DEOGEN2
Benign
0.25
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.0099
N
LIST_S2
Benign
0.58
T
MetaRNN
Benign
0.0020
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.14
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.13
N
REVEL
Benign
0.16
Sift
Benign
0.091
T
Sift4G
Benign
0.27
T
Polyphen
0.65
P
Vest4
0.086
MVP
0.51
MPC
0.19
ClinPred
0.0092
T
GERP RS
-1.5
Varity_R
0.047
gMVP
0.20

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: rs11466018; hg19: chr16-3304739; API