chr16-3248947-G-C

Variant names:

• chr16-3248947-G-C
• rs11466026
• NM_000243.3:c.1318C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000243.3(MEFV):​c.1318C>G​(p.Gln440Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,194 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q440K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 1.97
• Publications: 13 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072651207).
• BP6: Variant 16-3248947-G-C is Benign according to our data. Variant chr16-3248947-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36499.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1318C>G	p.Gln440Glu	missense	Exon 4 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.685C>G	p.Gln229Glu	missense	Exon 3 of 9	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1318C>G	p.Gln440Glu	missense	Exon 4 of 10	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.685C>G	p.Gln229Glu	missense	Exon 3 of 9	ENSP00000438711.1
	MEFV	ENST00000539145.5	TSL:1	n.278-1701C>G		intron	N/A	ENSP00000444471.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00119 AC: 299 AN: 251484 AF XY: 0.000927

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000373 AC: 545 AN: 1461866 Hom.: 3 Cov.: 33 AF XY: 0.000318 AC XY: 231 AN XY: 727240

African (AFR) AF: 0.0108 AC: 361 AN: 33476

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1112004

Other (OTH) AF: 0.000944 AC: 57 AN: 60394

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.00358 AC XY: 267 AN XY: 74484

African (AFR) AF: 0.0110 AC: 458 AN: 41578

American (AMR) AF: 0.00497 AC: 76 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.000205 Hom.: 1

Bravo AF: 0.00411

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Apr 22, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.1318C>G; p.Gln440Glu variant (rs11466026) has been described in an individual with periodic fever adenitis pharyngitis aphthous ulcer syndrome (see link below), but has been described as likely benign due to allele frequency and prediction of functional impact (Accetturo 2020, Moradian 2017). The variant is reported in the ClinVar database (Variation ID: 36499) and is reported in the African population with an allele frequency of 1.2% (297/24962 alleles including 1 homozygote) in the Genome Aggregation Database. The glutamine at codon 440 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.124). Although this variant has been described with a relatively high population frequency, we cannot exclude the possibility that this is a mild pathogenic variant. However, given the lack of clinical and functional data, the significance of the p.Gln440Glu variant is uncertain at this time. References: Link to MEFV Q440E in Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 Accetturo M et al. Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever. Rheumatology (Oxford). 2020 Apr 1;59(4):754-761. PMID: 31411330. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647.

Oct 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in InFevers database in a patient with periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome (Cazeneuve et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 29178647, 28421071, 25760918, 24117178)

Familial Mediterranean fever Uncertain:1 Benign:2

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 17, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

Jun 03, 2022

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 4 p.Gln440Glu (c.1318C>G): This variant has not been reported in the literature but has been identified in 1 individual with PFAPA (periodic fevers with apthous stomatits, pharyngitis and adenitis) syndrome in the Infevers database (https://infevers.umai-montpellier.fr/). This variant is present in 1% (297/24962) of African alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3298947-G-C). This variant is present in ClinVar (Variation ID:36499). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Nov 22, 2019

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 4 p.Gln440Glu (c.1318C>G): This variant has not been reported in the literature but has been identified in 1 individual with PFAPA (periodic fevers with apthous stomatits, pharyngitis and adenitis) syndrome in the Infevers database (https://infevers.umai-montpellier.fr/). This variant is present in 1% (297/24962) of African alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3298947-G-C). This variant is present in ClinVar (Variation ID:36499). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

not specified Benign:1

May 22, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEFV c.1318C>G (p.Gln440Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251484 control chromosomes, predominantly at a frequency of 0.013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is close to that estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.013 vs 0.022), suggestive of a benign outcome. c.1318C>G has been reported in the literature as a likely benign variant using Rare Exome Variant Ensemble Learner (REVEL), a recently developed variant metapredictor tool. This proposed classification has also been validated by the INFEVERS database (example, Accetturo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.

See cases Benign:1

Apr 05, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: BP4, BP6

Autoinflammatory syndrome Benign:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.34	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.48
MVP		0.75
MPC		0.13
ClinPred		0.0097	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.16
Mutation Taster		=69/31	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

Other links and lift over

dbSNP: rs11466026; hg19: chr16-3298947;