16-3249468-C-T

Position:

chr16-3249468-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000243.3(MEFV):c.1223G>A(p.Arg408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,052 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R408L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 165 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:6O:1

Conservation

PhyloP100: -0.571

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 Benign. Variant got -9 ACMG points.

BP6

Variant 16-3249468-C-T is Benign according to our data. Variant chr16-3249468-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Likely_pathogenic=1, not_provided=1, Benign=2, Uncertain_significance=10}. Variant chr16-3249468-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0115 (1752/152326) while in subpopulation EAS AF= 0.055 (285/5182). AF 95% confidence interval is 0.0498. There are 28 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	3/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.590G>A	p.Arg197Gln	missense_variant	2/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	3/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1752

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00475

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00930

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0132

AC:

3314

AN:

250794

Hom.:

AF XY:

0.0138

AC XY:

1870

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.0530

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00813

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00991

AC:

14481

AN:

1461726

Hom.:

165

Cov.:

AF XY:

0.0101

AC XY:

7344

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00406

Gnomad4 AMR exome

AF:

0.00561

Gnomad4 ASJ exome

AF:

0.0301

Gnomad4 EAS exome

AF:

0.0497

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.00739

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0115

AC:

1752

AN:

152326

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

928

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00469

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.0550

Gnomad4 SAS

AF:

0.0176

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.00931

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00364

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.0128

AC:

1554

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.00925

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:5Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2024	See Variant Classification Assertion Criteria. -
Likely pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MEFV p.Arg408Gln variant is a well-studied variant in association with Familial Mediterranean Fever (FMF) and has been identified in 159 of 8198 proband chromosomes from multiple patients with the FMF phenotype (freq=0.019), however the role of this variant in disease is unclear (Cazeneuve_1999_PMID:10364520; Bonyadi_2009_PMID: 19863562; Migita_2014_PMID:24797171; Tsuchiya-Suzuki_2009_PMID:19531756; Migita_2012_PMID:22467954; De Pieri_2015_PMID:25866490; Lainka_2012_PMID:22903357; Berdeli_2011_PMID:21413889; Migita_2016_PMID:27473114). The variant was reported in dbSNP (ID: rs11466024), LOVD 3.0 and ClinVar (classified in relation to FMF as benign [Prevention Genetics, 2017], likely benign [Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, 2015], Likely pathogenic [EGL Genetic Diagnostics, 2017], Pathogenic [GeneReviews, 2016], Uncertain significance [GeneDx 2017; Praxis fuer Humar 2016; Invitae 2018; Integrated Genetics/Laboratory Corporation of America 2016; OMIM 2013; Integrated Genetics/Laboratory Corporation of America 2015]). The variant was not identified in the Cosmic database. The variant was identified in control databases in 3771 of 282186 chromosomes (53 homozygous) at a frequency of 0.013364 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: East Asian in 1072 of 19934 chromosomes (freq: 0.05378), Ashkenazi Jewish in 301 of 10342 chromosomes (freq: 0.0291), South Asian in 455 of 30606 chromosomes (freq: 0.01487), European (Finnish) in 363 of 25074 chromosomes (freq: 0.01448), Other in 94 of 7204 chromosomes (freq: 0.01305), European (non-Finnish) in 1175 of 128692 chromosomes (freq: 0.00913), Latino in 208 of 35416 chromosomes (freq: 0.005873), and African in 103 of 24918 chromosomes (freq: 0.004134). The R408Q variant is often found as a complex allele with the MEFV P369S variant. Bonyadi et al. (2009) identified the R408Q variant in 7/524 Azeri Turkish FMF patients as a complex allele with P369S; 4 of these patients were also compound heterozygous for another MEFV variant (Bonyadi_2009_PMID: 19863562). Migita et al. (2014) also identified the variant as a complex allele with P369S variant in 9/178 patients with typical FMF and 28/133 patients with atypical FMF; in 8 of these typical FMF and 15 of these atypical FMF patients the variant was present in the compound heterozygous state with at least one other MEFV variant (Migita_2014_PMID:24797171). A family with a severe autoinflammatory phenotype underwent testing of a 120 gene inflammasome-related panel which revealed a P369S/R408Q complex allele in the MEFV gene inherited from the father and found in both affected children as well as a T577A in the MEFV gene inherited from the affected mother and also found in both affected children (Stoffels_2014_PMID:23505238). Ryan et al. (2010) identified 35/40 symptomatic and 4 asymptomatic FMF family members with the R408Q/P369S complex allele. Functional studies of these variants did not demonstrate a significant difference from the wildtype in the ability of pyrin to bind to PSTPIP1, therefore the role of these variants in FMF and their potential functional impact is not known (Ryan_2010_PMID: 19934105). The variant occurs outside of the splicing consensus sequence however 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5â€šÃ„Ã´ splice site. The p.Arg408 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, 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 uncerta -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2023	- -

Familial Mediterranean fever

Uncertain:4Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2022	Variant summary: MEFV c.1223G>A (p.Arg408Gln) results in a conservative amino acid change located in the B-box-type zinc finger (IPR000315) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.45 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. When examined across all populations represented in the gnomAD database, the variant did not exceed the estimated maximal expected allele frequency for a disease causing MEFV allele however, in the European sub-cohort, 20 homozygous occurrences were observed, suggesting a benign nature for the variant across ethnicities. c.1223G>A has been extensively reported in databases and in the literature in individuals affected with Familial Mediterranean Fever or unexplained fevers, frequently as part of a haplotype with p.P369S (example, Ryan_2010, Migita_2014, Stoffels_2014, Pieri_2015, Hageman_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. This haplotype has been reported in the homozygous state in controls as well (3 occurrences in 1000G) supporting the neutral nature of the complex allele. In two families (Feng 2009), the variant or its complex with P369S was shown to not co-segregate in all affected family members. The complex variant was also found in compound heterozygous state with a known pathogenic variant in unaffected parents (Moussa_2013). At-least one functional study further supports a neutral nature for the variant. This substitution is located in exon 3 encoding a B-box domain and is necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1) (Ryan_2010). The ability of the MEFV to bind PSTPIP1 was not affected by the variant in isolation or as a part of a complex allele. Additionally, in silico structural modeling predicted that the variant does not result in alteration to the secondary structure elements potentially required to maintain the structural integrity of the B-box domain (Ryan_2010). Multiple clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These submitters have reported the variant with conflicting assessments ranging from Likely Benign (n=3), Uncertain Significance (n=5), Likely Pathogenic (n=2) to Pathogenic (n=1). Of note, one of these submitters has recently re-evaluated this variant from Likely Pathogenic to a VUS but not updated their ClinVar record. We have considered their assessment as a VUS in this context. Some submitters have provided overlapping evidence utilized in the context of our evaluation. We have followed this variant for over four years and previously classified it as a VUS-possibly benign variant. In our review of published evidence spanning over 20 years (1999-2019), the majority of evidence appears to point toward a non-pathogenic outcome however more data is required to conclusively determine the clinical consequences of this variant. Therefore, based on the evidence outlined above, this variant in isolation retains its classification as likely benign. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2017

The p.R408Q variant (also known as c.1223G>A), located in coding exon 3 of the MEFV gene, results from a G to A substitution at nucleotide position 1223. The arginine at codon 408 is replaced by glutamine, an amino acid with highly similar properties. This variant is often seen in cis with p.P369S, and has been identified in individuals with typical and atypical familial Mediterranean fever (FMF) as well as in healthy controls (Cazeneuve C et al. Am. J. Hum. Genet., 1999 Jul;65:88-97; Feng J et al. PLoS ONE, 2009 Dec;4:e8480; Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). The p.P369S and p.R408Q variants were found to be in strong linkage disequilibrium; genetic and functional data suggest that the p.[P369S; R408Q] complex allele is unlikely to represent a classic FMF disease-associated mutation, and is more likely to be a high frequency low-penetrance mutation (Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8; Migita K et al. Medicine (Baltimore), 2014 May;93:158-64). Based on data from ExAC, the A allele has an overall frequency of approximately 1.304% (1375/105484) total alleles studied. The highest observed frequency was 5.315% (418/7864) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence to date, the clinical significance of this alteration remains unclear (Ryan et al. Rheum Dis. 2010;69(7):1383-8). -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.23

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.49

T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.035

Sift

Benign

0.23

T;T;T;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

0.26

B;.;.;.

Vest4

0.063

MPC

0.14

ClinPred

0.0014

GERP RS

-2.5

Varity_R

0.038

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -1

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