16-3254532-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000243.3(MEFV):c.536G>A(p.Ser179Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,555,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. S179I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: -0.462

Publications

8 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073755383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.536G>A	p.Ser179Asn	missense_variant	Exon 2 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 link	c.277+1779G>A		intron_variant	Intron 1 of 8		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.536G>A	p.Ser179Asn	missense_variant	Exon 2 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152230

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:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000281

AC:

AN:

156324

AF XY:

0.000394

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

147

AN:

1403068

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

109

AN XY:

694008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32152

American (AMR)

AF:

0.00

AC:

AN:

36698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.00

AC:

AN:

36930

South Asian (SAS)

AF:

0.00168

AC:

137

AN:

81770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41840

Middle Eastern (MID)

AF:

0.000229

AC:

AN:

4366

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

1085952

Other (OTH)

AF:

0.0000688

AC:

AN:

58136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.0000656

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00186

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000219

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Uncertain:5

Jul 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 179 of the MEFV protein (p.Ser179Asn). This variant is present in population databases (rs104895125, gnomAD 0.2%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 20721559, 29579081). ClinVar contains an entry for this variant (Variation ID: 664952). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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. -

Jan 19, 2023

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEFV c.536G>A (p.Ser179Asn) missense variant results in the substitution of serine at amino acid position 179 with asparagine. This variant has been reported in an individual with familial Mediterranean fever (FMF) who also carried another missense variant (phase unknown) (PMID: 20721559). The c.536G>A variant was also identified in a homozygous state in two individuals with rheumatic heart disease. This variant resides between the PYD and BBox domain and 3-D protein modelling show that the c.536G>A variant impacts the protein structure and conformation as compared to normal protein (DOI: 10.4172/2155-9899.1000382). A different missense change at the same amino acid residue has also been reported in a compound heterozygous state with a pathogenic variant in a father and son with FMF (PMID: 14636645). This variant is reported in the Genome Aggregation Database in nine alleles at a frequency of 0.00186 in the South Asian population (version 3.1.2). Based on the available evidence, the c.536G>A (p.Ser179Asn) variant is classified as a variant of uncertain significance for familial Mediterranean fever. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense variant c.536G>Ap.Ser179Asn in the MEFV gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.03% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance/Likely benign. However, no details are available for independent assessment. The amino acid Ser at position 179 is changed to a Asn changing protein sequence and it might alter its composition and physico- chemical properties. Multiple lines of computational evidence Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism predict no damaging effect on protein structure and function for this variant. . The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Feb 08, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:4

May 14, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial Mediterranean fever, autosomal dominant

Uncertain:1Benign:1

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense variant c.536G>Ap.Ser179Asn in MEFV gene has been reported previously in heterozygous state in individuals with familial Mediterranean fever Aita A, et al., 2018, Fujikura K, et al., 2015, Cornelius N, Duno M, 2011. The p.Ser179Asn variant is reported with 0.03% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Benign/ Uncertain Significance multiple submissions. However, study on multiple affected individuals and functional impact of the variant is not available. The amino acid Ser at position 179 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance. -

Feb 08, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Jan 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acute febrile neutrophilic dermatosis

Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.48

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.29

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.41

M_CAP

Benign

0.018

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-0.46

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.83

REVEL

Benign

0.046

Sift

Benign

0.30

Sift4G

Benign

0.40

Polyphen

0.0060

Vest4

0.099

MutPred

0.24

Loss of phosphorylation at S179 (P = 0.0023);

MVP

0.56

MPC

0.11

ClinPred

0.017

GERP RS

-1.5

Varity_R

0.059

gMVP

0.17

Mutation Taster

=82/18

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over