rs61754767

chr16-3256464-G-Achr16-3256464-G-Cchr16-3256464-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000243.3(MEFV):c.124C>T(p.Arg42Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R42R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 0.209

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008853793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.124C>T	p.Arg42Trp	missense_variant	1/10	ENST00000219596.6
MEFV	NM_001198536.2	c.124C>T	p.Arg42Trp	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.124C>T	p.Arg42Trp	missense_variant	1/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

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: 0.00191

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251476 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135920

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.000136 AC XY: 99 AN XY: 727246

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74464

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 03, 2020	The MEFV c.124C>T; p.Arg42Trp variant (rs61754767) is reported in the medical literature in one individual with familial Mediterranean fever (Touitou 2001). The variant protein is also described as having at least some altered function (Vajjhala 2014), but the variant is also described as not occurring in the same region as known pathogenic variants (Moradian 2017). The variant is reported in the ClinVar database (Variation ID: 234347). This variant is found in the population with an overall allele frequency of 0.4% (97/24,032 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. REFERENCES Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 Jul;9(7):473-83. 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. Vajjhala PR et al. Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. J Biol Chem. 2014 Aug 22;289(34):23504-19. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	Observed in the heterozygous state with and without other variants in patients with familial Mediterranean fever and was observed at a frequency of 0.5% in a study of Armenian patients with FMF (Touitou et al., 2001; Sarkisian et al., 2005; Moradian et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14527383, 21228398, 11464238, 19505404, 25006247, 15641782, 14527388, 25451010, 20485448, 15951859, 15720244, 15502081, 12496512, 29178647, 15720238) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial Mediterranean fever Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 11, 2022

Variant summary: MEFV c.124C>T (p.Arg42Trp) results in a non-conservative amino acid change located in the DAPIN domain (also called pyrin domain (PYD), IPR004020) which is a protein-protein interaction domain involved in inflammasome assembly (Vajjhala_2014). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 282866 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.004, including 1 homozygote in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.004 vs 0.022), allowing no conclusion about variant significance. c.124C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever (FMF), however without strong evidence for pathogenicity (e.g. Moradian_2017). Therefore these data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence on protein function, demonstrating an increased protein stability, possibly decreased auto-inhibition, but also a decreased protein-protein interaction (with ASC) that is important for the inflammasome assembly; the authors of this study hypothesized that the overall effects of the variant might contribute to FMF by facilitating activation of the pyrin inflammasome (Vajjhala_2014). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, four classifying the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0089	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L;.;L;L
MutationTaster	Benign	0.52	D;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.31
MVP		0.85
MPC		0.25
ClinPred		0.062	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.55

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: rs61754767; hg19: chr16-3306464;