16-3254380-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000243.3(MEFV):c.688G>A(p.Glu230Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,614,138 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. E230Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (9 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:1 O:1
• Conservation: PhyloP100: 0.525

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038651735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.688G>A	p.Glu230Lys	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+1931G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.688G>A	p.Glu230Lys	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000629 AC: 157 AN: 249694 Hom.: 1 AF XY: 0.000925 AC XY: 125 AN XY: 135160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000713

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000358 AC: 523 AN: 1461788 Hom.: 9 Cov.: 32 AF XY: 0.000528 AC XY: 384 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00509

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000659 AC: 80

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Pathogenic:1 Uncertain:4 Benign:1 Other:1

Pathogenic, flagged submission	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MEFV: PM3:Strong, PM2:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	The E230K missense mutation in the MEFV gene has been reported previously in association with Familial Mediterranean Fever (FMF) (Touitou et al., 2001, Timmann et al., 2001; Ceylan et al., 2012). It was also published in association with multiple sclerosis in a patient with symptoms and positive family history of FMF (Blaschek et al., 2010). Per the 1000 Genomes Consortium, E230K was observed at a frequency of 1.74%, 3/172 alleles, in individuals of Bengali ancestry (McVean et al., 2012). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 17, 2023

Variant summary: MEFV c.688G>A (p.Glu230Lys) results in a 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 0.00063 in 249694 control chromosomes, predominantly at a frequency of 0.0047 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00063 vs 0.022), allowing no conclusion about variant significance. c.688G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals reportedly meeting the clinical diagnostic criteria for Familial Mediterranean Fever (FMF) (example, Timmann_2001, Kallinich_2010, Berdelli_2011, Lainka_2012, Omenetti_2013, Gohar_2016, Arpaci_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as VUS (n=8) (Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MEFV NM_000243.2 exon 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. 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, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.688G>A p.Glu230Lys variant in MEFV gene has been reported previously in compound heterozygous state in individuals affected with Familial Mediterranean fever FMF Timmann et al., 2001. This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glu at position 230 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu230Lys in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 27, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

May 14, 2019

MEFV NM_000243.2 exon 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.042	D
Polyphen		0.062	B
Vest4		0.79
MVP		0.66
MPC		0.13
ClinPred		0.022	T
GERP RS		1.9
Varity_R		0.061
gMVP		0.58

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

Other links and lift over

dbSNP: rs104895080; hg19: chr16-3304380; COSMIC: COSV54818298;