rs11466023

Positions:

• chr16-3249586-G-A
• chr16-3249586-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000243.3(MEFV):​c.1105C>T​(p.Pro369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,188 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 33)
  • Exomes 𝑓: 0.010 (215 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:13 B:5 O:1
• Conservation: PhyloP100: 1.69

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018258095).
• BP6: Variant 16-3249586-G-A is Benign according to our data. Variant chr16-3249586-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2551.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Likely_pathogenic=1, not_provided=1, Benign=2, Uncertain_significance=10}. Variant chr16-3249586-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0122 (1861/152322) while in subpopulation EAS AF= 0.0729 (377/5168). AF 95% confidence interval is 0.0669. There are 31 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1105C>T	p.Pro369Ser	missense_variant	3/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.472C>T	p.Pro158Ser	missense_variant	2/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1105C>T	p.Pro369Ser	missense_variant	3/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1861 AN: 152204 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0146 AC: 3651 AN: 250836 Hom.: 75 AF XY: 0.0151 AC XY: 2045 AN XY: 135662

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.0700

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0103 AC: 15105 AN: 1461866 Hom.: 215 Cov.: 32 AF XY: 0.0105 AC XY: 7651 AN XY: 727234

Gnomad4 AFR exome AF: 0.00406

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.0621

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0122 AC: 1861 AN: 152322 Hom.: 31 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74492

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.0729

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.00944

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0113 Hom.: 51

Bravo AF: 0.0114

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.0142 AC: 1720

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00925

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:13 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:6 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MEFV p.Pro369Ser variant a well-studied variant in association with Familial Mediterranean Fever (FMF) and has been identified in 104 of 5484 proband chromosomes from multiple patients with the FMF phenotype (freq=0.019), however the role of this variant in disease is unclear (Migita_2014_PMID:24797171; Cazeneuve_1999_PMID:10364520; Aksentijevich_1999_PMID:10090880; Caglayan_2010_PMID:19934083; Migita_2012_PMID:22467954; Berdeli_2011_PMID:21413889). The variant was also identified in dbSNP (ID: rs11466023), LOVD 3.0 and ClinVar (classified in relation to FMF as benign [Prevention Genetics], likely pathogenic ([EGL Genetic Diagnostics, 2014], pathogenic [GeneReviews, 2016],  Uncertain significance [OMIM 2013; Integrated Genetics/Laboratory Corporation of America 2015; Integrated Genetics/Laboratory Corporation of America 2017; Invitae 2018; ARUP Laboratories 2017; GeneDx 2017; Praxis fuer Humangenetik Tuebingen 2016]). The variant was not identified in the Cosmic database. The variant was identified in control databases in 4150 of 282228 chromosomes (86 homozygous) at a frequency of 0.014704 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 1425 of 19936 chromosomes (freq: 0.07148), Ashkenazi Jewish in 302 of 10358 chromosomes (freq: 0.02916), South Asian in 472 of 30616 chromosomes (freq: 0.01542), European (Finnish) in 363 of 25100 chromosomes (freq: 0.01446), Other in 96 of 7214 chromosomes (freq: 0.01331), European (non-Finnish) in 1178 of 128636 chromosomes (freq: 0.009158), Latino in 213 of 35426 chromosomes (freq: 0.006013), and African in 101 of 24942 chromosomes (freq: 0.004049). The P369S variant is often found as a complex allele with the MEFV R408Q variant. Bonyadi et al. (2009) identified the P369 variant in 7/524 Azeri Turkish FMF patients as a complex allele with R408Q; 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 R408Q 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). Ryan et al. (2010) identified 35/40 symptomatic and 4 asymptomatic FMF family members with the R408Q/P369S complex allele, with the other 5/40 symptomatic family members only having the P369S variant. 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). There are also multiple case reports in which patients with atypical or late onset FMF are found to have the p.Pro369Ser variant along with other MEFV variants (Kitade_2015_PMID:26027984; Yamagami_2017_PMID:28001092). Hannan et al reported an atypical case of FMF with a late onset of attacks who was found to have the P369S/R408Q complex allele as well as the E148Q MEFV variant; this suggests a highly variable clinical phenotype of FMF (Hannan_2012_PMID:22906030). The p.Pro369 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. Thi -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2019	- -
Likely pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2024	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 10, 2020	- -

Familial Mediterranean fever Uncertain:5 Benign:1 Other:1

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, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 23, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: MEFV c.1105C>T (p.Pro369Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 253268 control chromosomes, predominantly at a frequency of 0.07 within the East Asian subpopulation in the gnomAD database, including 54 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 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. Additionally, the variant was found with even higher frequencies in the 1000 Genomes Project within some East Asian subpopulations, further supporting that this variant is likely a benign polymorphism (Moradian 2017). Due to its high frequency, the variant, c.1105C>T, has been reported in the literature in sequencing studies of numerous individuals affected with FMF, generally in combination with one or more other MEFV variants (e.g. Ryan_2010, Caglayan_2010, Berdeli_2011, Migita 2016, Hoang_2019). Many of the earlier reports suffer from a lack of extensive genotyping limited to small panels of variants in the MEFV gene. However, a recent study evaluating the prevalence of the disease in the Japanese population (Migita 2016) found no significant difference in allele frequencies between FMF patients (8.6%; 33/384 alleles) and healthy subjects (6.2%; 13/210 alleles). The variant was reported in a family in two asymptomatic individuals with another pathogenic MEFV variant (c.1437C>G (p.Phe479Leu) or c.2040G>C (p.Met680Ile)) in trans (Moussa_2013), providing supporting evidence for a benign role. Co-immunoprecipitation studies demonstrated that the variant does not affect the binding of pyrin to the PSTPIP1 protein (Ryan_2010). Fourteen ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=11), likely benign (n=2) or likely pathogenic (n =1). At-least one submitting clinical diagnostic laboratory has re-classified this variant as likely benign since its last evaluation by our laboratory. Some sumbitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2017

The p.P369S variant (also known as c.1105C>T), located in coding exon 3 of the MEFV gene, results from a C to T substitution at nucleotide position 1105. The proline at codon 369 is replaced by serine, an amino acid with similar properties. This variant is often seen in cis with p.R408Q, and has been identified in individuals with typical and atypical familial Mediterranean fever (FMF) as well as in healthy controls (Aksentijevich I et al. Am. J. Hum. Genet., 1999 Apr;64:949-62; 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 T allele has an overall frequency of approximately 1.437% (1518/105622) total alleles studied. The highest observed frequency was 7.026% (550/7828) of East Asian alleles. This amino acid position is well conserved in limited vertebrate species; however, serine is the reference amino acid is several species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Based on the available evidence to date, the clinical significance of this alteration remains unclear (Ryan JG et al. Ann. Rheum. Dis., 2010 Jul;69:1383-8). -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.036	D;D;T;T
Sift4G	Benign	0.080	T;D;T;D
Polyphen		0.96	D;.;.;.
Vest4		0.14
MPC		0.46
ClinPred		0.035	T
GERP RS		1.1
Varity_R		0.088
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11466023; hg19: chr16-3299586;