rs224207

Variant names:

• chr16-3247175-T-C
• rs224207
• NM_000243.3:c.1428A>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.1428A>G​(p.Gln476Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,124 control chromosomes in the GnomAD database, including 262,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26194 hom., cov: 32)
  • Exomes 𝑓: 0.56 (236098 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.03
• 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=-0.81).
• BP6: Variant 16-3247175-T-C is Benign according to our data. Variant chr16-3247175-T-C is described in ClinVar as Benign. ClinVar VariationId is 255615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1428A>G	p.Gln476Gln	synonymous_variant	Exon 5 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.795A>G	p.Gln265Gln	synonymous_variant	Exon 4 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1428A>G	p.Gln476Gln	synonymous_variant	Exon 5 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88598 AN: 151460 Hom.: 26154 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.608 AC: 152877 AN: 251442 AF XY: 0.603

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.658

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.565 AC: 825635 AN: 1461544 Hom.: 236098 Cov.: 63 AF XY: 0.568 AC XY: 412707 AN XY: 727090

African (AFR) AF: 0.647 AC: 21675 AN: 33478

American (AMR) AF: 0.725 AC: 32435 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14383 AN: 26132

East Asian (EAS) AF: 0.639 AC: 25369 AN: 39696

South Asian (SAS) AF: 0.714 AC: 61554 AN: 86248

European-Finnish (FIN) AF: 0.562 AC: 30042 AN: 53412

Middle Eastern (MID) AF: 0.554 AC: 3195 AN: 5764

European-Non Finnish (NFE) AF: 0.542 AC: 602514 AN: 1111702

Other (OTH) AF: 0.571 AC: 34468 AN: 60390

GnomAD4 genome AF: 0.585 AC: 88697 AN: 151580 Hom.: 26194 Cov.: 32 AF XY: 0.589 AC XY: 43660 AN XY: 74064

African (AFR) AF: 0.643 AC: 26545 AN: 41292

American (AMR) AF: 0.622 AC: 9476 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1916 AN: 3466

East Asian (EAS) AF: 0.642 AC: 3301 AN: 5142

South Asian (SAS) AF: 0.727 AC: 3501 AN: 4816

European-Finnish (FIN) AF: 0.555 AC: 5826 AN: 10492

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36422 AN: 67832

Other (OTH) AF: 0.570 AC: 1203 AN: 2110

Alfa AF: 0.557 Hom.: 18189

Bravo AF: 0.594

Asia WGS AF: 0.701 AC: 2439 AN: 3478

EpiCase AF: 0.533

EpiControl AF: 0.529

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Jul 12, 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. -

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	-0.81
CADD	Benign	0.82
DANN	Benign	0.23
PhyloP100		-1.0
Mutation Taster		=99/1	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: rs224207; hg19: chr16-3297175; COSMIC: COSV54819266;