rs224213

chr16-3249749-G-Achr16-3249749-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):c.942C>T(p.Arg314=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,414 control chromosomes in the GnomAD database, including 276,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29459 hom., cov: 32)
  • Exomes 𝑓: 0.58 (247041 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: -1.73

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-3249749-G-A is Benign according to our data. Variant chr16-3249749-G-A is described in ClinVar as [Benign]. Clinvar id is 36515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3249749-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.942C>T	p.Arg314=	synonymous_variant	3/10	ENST00000219596.6
MEFV	NM_001198536.2	c.309C>T	p.Arg103=	synonymous_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.942C>T	p.Arg314=	synonymous_variant	3/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93658 AN: 151924 Hom.: 29416 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.601

GnomAD3 exomes AF: 0.628 AC: 155507 AN: 247588 Hom.: 50008 AF XY: 0.622 AC XY: 83443 AN XY: 134182

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.720

Gnomad SAS exome AF: 0.742

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.584

GnomAD4 exome AF: 0.577 AC: 843633 AN: 1461372 Hom.: 247041 Cov.: 60 AF XY: 0.580 AC XY: 421488 AN XY: 726982

Gnomad4 AFR exome AF: 0.718

Gnomad4 AMR exome AF: 0.737

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.696

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.576

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.593

GnomAD4 genome AF: 0.617 AC: 93764 AN: 152042 Hom.: 29459 Cov.: 32 AF XY: 0.622 AC XY: 46237 AN XY: 74316

Gnomad4 AFR AF: 0.712

Gnomad4 AMR AF: 0.650

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.706

Gnomad4 SAS AF: 0.743

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.602

Alfa AF: 0.566 Hom.: 35000

Bravo AF: 0.626

Asia WGS AF: 0.745 AC: 2593 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.539

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Benign:5

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 75.895% in ExAC) based on the frequency threshold of 1.904% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.15
Dann	Benign	0.47

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: rs224213; hg19: chr16-3299749; COSMIC: COSV54818607; COSMIC: COSV54818607;