chr16-3249749-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000243.3(MEFV):c.942C>T(p.Arg314Arg) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:15

Conservation

PhyloP100: -1.73

Publications

34 publications found

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 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)

MEFV links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 36515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.942C>T	p.Arg314Arg	synonymous_variant	Exon 3 of 10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 link	c.309C>T	p.Arg103Arg	synonymous_variant	Exon 2 of 9		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.942C>T	p.Arg314Arg	synonymous_variant	Exon 3 of 10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.616

AC:

93658

AN:

151924

Hom.:

29416

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.628

AC:

155507

AN:

247588

AF XY:

0.622

show subpopulations

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 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.:

AF XY:

0.580

AC XY:

421488

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.718

AC:

24018

AN:

33474

American (AMR)

AF:

0.737

AC:

32917

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15125

AN:

26122

East Asian (EAS)

AF:

0.696

AC:

27636

AN:

39684

South Asian (SAS)

AF:

0.728

AC:

62777

AN:

86238

European-Finnish (FIN)

AF:

0.576

AC:

30772

AN:

53392

Middle Eastern (MID)

AF:

0.572

AC:

3297

AN:

5768

European-Non Finnish (NFE)

AF:

0.550

AC:

611300

AN:

1111658

Other (OTH)

AF:

0.593

AC:

35791

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

19424

38848

58273

77697

97121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17378

34756

52134

69512

86890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.617

AC:

93764

AN:

152042

Hom.:

29459

Cov.:

AF XY:

0.622

AC XY:

46237

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.712

AC:

29521

AN:

41488

American (AMR)

AF:

0.650

AC:

9923

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

2030

AN:

3470

East Asian (EAS)

AF:

0.706

AC:

3652

AN:

5170

South Asian (SAS)

AF:

0.743

AC:

3581

AN:

4820

European-Finnish (FIN)

AF:

0.570

AC:

6021

AN:

10560

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.548

AC:

37213

AN:

67948

Other (OTH)

AF:

0.602

AC:

1271

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1844

3688

5533

7377

9221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.576

Hom.:

94533

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:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Benign:5

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

- -

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 12, 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. -

not provided

Uncertain:1Benign:3

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: 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. -

Mar 03, 2015

GeneDx

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

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

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 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.15

(source)

DANN

Benign

0.47

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over