chr16-3243529-C-T

Position:

• chr16-3243529-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000243.3(MEFV):​c.1958G>A​(p.Arg653His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:2
• Conservation: PhyloP100: 0.522

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3243529-C-T is Pathogenic according to our data. Variant chr16-3243529-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1958G>A	p.Arg653His	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*162G>A		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1958G>A	p.Arg653His	missense_variant	10/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251200 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135764

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727066

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74438

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Pathogenic:5 Uncertain:1 Other:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 15, 2019	- -
Uncertain significance, flagged submission	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jun 08, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 653 of the MEFV protein (p.Arg653His). This variant is present in population databases (rs104895085, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 11470495, 16378925, 19479870, 21413889, 24469716, 29159471, 31989427; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2553). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2017	Variant summary: The MEFV c.1958G>A (p.Arg653His) variant located in the SPRY domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 2/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 6/121204 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple publications have cited the variant in affected individuals in whom a second mutation not identified. Of note, this variant was reported in one affected individual who met the Tel-Hashomer criteria for a diagnosis of MEFV as a compound heterozygote along with p.M694V. The unaffected mother and brother were carriers for the variant of interest. In addition, Booty_2009 reports a clinically diagnosed FMF affected sib-pair that each carry only the variant of interest following a comprehensive search for a second mutation in the MEFV gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, although no in-vitro or in-vivo functional studies supporting a damaging outcome for this variant have been reported, the ascertained evidence has been weighted to classify this variant as Pathogenic. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2016	The R653H pathogenic variant in the MEFV that has been previously reported in association with Familial Mediterranean Fever (FMF) (Schaner et al., 2001; Timmann et al., 2001; Booty et al., 2009; Lazarin et al., 2013). It has also been observed in patients with juvenile idiopathic arthritis (Comak et al., 2013). The R653 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R653H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, a missense variant in a nearby residue (E656A) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 18, 2021	The MEFV c.1958G>A; p.Arg653His variant (rs104895085) has been described in the heterozygous state in several individuals with a clinical diagnosis of familial Mediterranean fever and at least once in the compound heterozygous state in an individual with an additional pathogenic variant (Berdeli 2011, Botty 2009, Comak 2013, Jeske 2013, Oztuzcu 2014, Schaner 2001, Shinar 2007, Timmann 2001). The variant is reported in the ClinVar database (Variation ID: 2553) and is listed in the general population with an overall allele frequency of 0.0035% (10/282,580 alleles) in the Genome Aggregation Database. The arginine at codon 653 occurs in the SPRY domain, is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). However, most pathogenic MEFV variants occur in the SPRY domain (Manukyan 2016). Based on available information, this variant is classified as likely pathogenic. References: Berdeli A et al. Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey? Genet Test Mol Biomarkers. 2011 Jul-Aug;15(7-8):475-82. Booty MG et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009 Jun;60(6):1851-61. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Jeske M et al. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. Klin Padiatr. 2013 Nov;225(6):325-30 Manukyan G and Aminov R Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever. Front. Microbiol. 2016 7:456. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. Schaner P et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet. 2001 Mar;27(3):318-21. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. Timmann C et al. Two novel mutations R653H and E230K in the Mediterranean fever gene associated with disease. Mutat Res. 2001 Aug 8;479(1-2):235-9. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 12, 2019	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	9.2
DANN	Benign	0.10
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.6	N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	4.7	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.45
MVP		0.32
MPC		0.14
ClinPred		0.024	T
GERP RS		1.6
Varity_R		0.39
gMVP		0.30

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: rs104895085; hg19: chr16-3293529; COSMIC: COSV105004010; COSMIC: COSV105004010;