chr16-3254746-T-G

Position:

chr16-3254746-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBP6

The NM_000243.3(MEFV):c.322A>C(p.Ser108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2O:1

Conservation

PhyloP100: 0.146

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

BP6

Variant 16-3254746-T-G is Benign according to our data. Variant chr16-3254746-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97515.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.322A>C	p.Ser108Arg	missense_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.277+1565A>C		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.322A>C	p.Ser108Arg	missense_variant	2/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000809

AC:

AN:

247174

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460468

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Uncertain:5Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 108 of the MEFV protein (p.Ser108Arg). This variant is present in population databases (rs104895103, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 16378925, 19786432, 29047407). ClinVar contains an entry for this variant (Variation ID: 97515). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000081). A missense variant is a common mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MEFV related disorder (PMID:16378925). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2022	Variant summary: MEFV c.322A>C (p.Ser108Arg) results in a non-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 8.1e-06 in 247374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322A>C has been reported in the literature in individuals affected with Periodic Fever Syndrome (e.g. Gattorno_2009, Federici_2012) and familial Mediterranean fever (e.g. Medlej-Hashim_2005, Omenetti_2014, Ozen_2014, Papa_2017), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with another pathogenic variant have been reported (example, Omenetti_2014) and observed at our laboratory (MEFV c.2177T>C, p.Val726Ala), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Furthermore, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of uncertain significance for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2019	The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound heterozygous with the pathogenic V726A allele (Federici 2012, Gattorno 2009, Kilinc 2016, Medlej-Hashim 2005). This variant is classified as uncertain in ClinVar (Variation ID: 97515). It is only observed in two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on currently available information, it is uncertain whether this variant is benign or disease-associated. REFERENCES Federici S et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis. 2012 Dec;71(12):1961-5. Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Kilinc M et al. The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int. 2016 Jan;36(1):25-31. Medlej-Hashim M et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	Observed in the heterozygous state in patients with MEFV-related periodic fever syndromes, often in individuals also heterozygous for the p.(V726A) variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Medlej-Hashim et al., 2005; Salehzadeh et al., 2014; Kilinc et al., 2016; Papa et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26215181, 25793047, 29047407, 23463692, 19786432, 22580583, 16378925, 33844039, El Hawary_2022) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2016

The p.S108R variant (also known as c.322A>C), located in coding exon 2 of the MEFV gene, results from an A to C substitution at nucleotide position 322. The serine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in two individuals with FMF; one individual also had the p.V726A pathogenic mutation and the second individual had two additional alterations in the MEFV gene. The phase of these alterations (whether in cis or trans) is not known (Medlej-Hashim M, Eur J Med Genet ; 48(4):412-20). This variant was previously reported in the SNPDatabase as rs104895103. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Acute febrile neutrophilic dermatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Familial Mediterranean fever, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Benign

3.3

DANN

Benign

0.84

DEOGEN2

Benign

0.31

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.67

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.40

Sift

Benign

0.071

Sift4G

Benign

0.072

Polyphen

0.87

Vest4

0.74

MutPred

0.74

Gain of solvent accessibility (P = 2e-04);

MVP

0.65

MPC

0.13

ClinPred

0.098

GERP RS

-1.4

Varity_R

0.056

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over