rs104895179

chr16-3254482-C-Achr16-3254482-C-Gchr16-3254482-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000243.3(MEFV):c.586G>T(p.Gly196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,587,236 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. G196R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (11 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: -0.403

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047331452).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000541 (776/1434888) while in subpopulation AFR AF= 0.0188 (616/32682). AF 95% confidence interval is 0.0176. There are 11 homozygotes in gnomad4_exome. There are 328 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.586G>T	p.Gly196Trp	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+1829G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.586G>T	p.Gly196Trp	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152232 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00122 AC: 248 AN: 203408 Hom.: 0 AF XY: 0.000848 AC XY: 96 AN XY: 113160

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.000485

Gnomad NFE exome AF: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000541 AC: 776 AN: 1434888 Hom.: 11 Cov.: 37 AF XY: 0.000460 AC XY: 328 AN XY: 712366

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.000987

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000706

Gnomad4 FIN exome AF: 0.000550

Gnomad4 NFE exome AF: 0.0000182

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00444 AC: 676 AN: 152348 Hom.: 6 Cov.: 33 AF XY: 0.00417 AC XY: 311 AN XY: 74498

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.00550

ESP6500AA AF: 0.00960 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00138 AC: 158

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29178647, 26990548, 22995991, 20044784, 24929125, 24263150, 32199921) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2021	The MEFV c.586G>T; p.Gly196Trp variant (rs104895179) is reported in the literature in several individuals with periodic fever or autoimmune syndromes (Bozgeyik 2020, Cantarini 2012, Oztuzcu 2014 ). However, the variant has also been reported in at least one individual with an alternate molecular explanation for disease (Gunesacar 2014). The variant is reported in the ClinVar database (Variation ID: 97532) and in the African population with an allele frequency of 1.7% (350/20,178 alleles including 2 homozygotes) in the Genome Aggregation Database. The glycine at codon 196 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.237). Although the allele frequency of this variant is higher than would be predicted for FMF, given the lack of clinical and functional data, the significance of the p.Gly196Trp variant is uncertain at this time. References: Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. PMID: 32199921. Cantarini L et al. Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene. Rheumatol Int. 2012 Feb;32(2):465-7. Gunesacar R et al. Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene. 2014 Aug 10;546(2):195-9 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2016	Variant Summary: The MEFV variant, c.586G>T (p.Gly196Trp), causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.20%, predominantly observed in the African subpopulation at a frequency of 2.4%. This frequency slightly exceeds the maximal expected allele frequency for a pathogenic variant in MEFV (2.2%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in at least 2 FMF patients, one of whom also had a common pathogenic mutation in the homozygous state (c.2082G>A, M694I; Gunesacar_2014), suggesting the variant of interest was not the causitive mutation in this individual. The variant has also been reported in atypical FMF patients and a Systemic Juvenile Idiopathic Arthritis patient, however the variant was the only detected variant in these patients. In addition, one reputable clinical lab has classified the variant as "benign", without evidence to independently evaluate. Taken together, this variant has been classified as a variant of uncertain significance, possibly benign variant, until additional information becomes available. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Familial Mediterranean fever, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 23, 2020

- -

MEFV-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2023

The MEFV c.586G>T variant is predicted to result in the amino acid substitution p.Gly196Trp. This variant has been reported in patients with Familial Mediterranean Fever (Jesus et al. 2012. PubMed ID: 22566169; Aydogan et al. 2013. PubMed ID: 23155201; Oztuzcu et al. 2014. PubMed ID: 24469716; Gunesacar et al. 2014. PubMed ID: 24929125; Bozgeyik et al. 2020. PubMed ID: 32199921) and systemic juvenile idiopathic arthritis (Cantarini et al. 2012. PubMed ID: 20044784). This variant is reported in 1.7% of alleles in individuals of African descent in gnomAD, including two homozygous individuals (http://gnomad.broadinstitute.org/variant/16-3304482-C-A), which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.79
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.46	P
Vest4		0.74
MVP		0.33
MPC		0.16
ClinPred		0.014	T
GERP RS		-2.3
Varity_R		0.070
gMVP		0.26

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: rs104895179; hg19: chr16-3304482;