16-3254654-T-C

Variant names:

• chr16-3254654-T-C
• rs224224
• NM_000243.3:c.414A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):​c.414A>G​(p.Gly138Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,608,252 control chromosomes in the GnomAD database, including 174,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G138G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17589 hom., cov: 33)
  • Exomes 𝑓: 0.45 (156797 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17 O:1
• Conservation: PhyloP100: -0.557
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• familial Mediterranean fever

  Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-3254654-T-C is Benign according to our data. Variant chr16-3254654-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.557 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.414A>G	p.Gly138Gly	synonymous_variant	Exon 2 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.277+1657A>G		intron_variant	Intron 1 of 8		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.414A>G	p.Gly138Gly	synonymous_variant	Exon 2 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71714 AN: 152054 Hom.: 17559 Cov.: 33

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.439 AC: 104601 AN: 238018 AF XY: 0.421

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.455 AC: 661840 AN: 1456084 Hom.: 156797 Cov.: 61 AF XY: 0.446 AC XY: 322865 AN XY: 724190

African (AFR) AF: 0.502 AC: 16765 AN: 33374

American (AMR) AF: 0.609 AC: 27068 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10500 AN: 26082

East Asian (EAS) AF: 0.147 AC: 5823 AN: 39642

South Asian (SAS) AF: 0.203 AC: 17515 AN: 86186

European-Finnish (FIN) AF: 0.505 AC: 25403 AN: 50298

Middle Eastern (MID) AF: 0.316 AC: 1816 AN: 5754

European-Non Finnish (NFE) AF: 0.478 AC: 530938 AN: 1110158

Other (OTH) AF: 0.432 AC: 26012 AN: 60152

GnomAD4 genome AF: 0.472 AC: 71803 AN: 152168 Hom.: 17589 Cov.: 33 AF XY: 0.468 AC XY: 34852 AN XY: 74404

African (AFR) AF: 0.506 AC: 21014 AN: 41544

American (AMR) AF: 0.554 AC: 8475 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1364 AN: 3468

East Asian (EAS) AF: 0.156 AC: 802 AN: 5150

South Asian (SAS) AF: 0.198 AC: 956 AN: 4828

European-Finnish (FIN) AF: 0.515 AC: 5465 AN: 10610

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32282 AN: 67954

Other (OTH) AF: 0.464 AC: 981 AN: 2112

Alfa AF: 0.414 Hom.: 2749

Bravo AF: 0.481

Asia WGS AF: 0.236 AC: 822 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 75% of patients studied by a panel of primary immunodeficiencies. Number of patients: 72. Only high quality variants are reported. -

Dec 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial Mediterranean fever Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

not provided Uncertain:1 Benign:2 Other:1

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 61.912% 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Benign:1

Sep 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever, autosomal dominant Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.1
DANN	Benign	0.40
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs224224; hg19: chr16-3304654; COSMIC: COSV54819820;