rs11466026

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000243.3(MEFV):c.1318C>G(p.Gln440Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,194 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q440K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 1.97

Publications

13 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):

autosomal recessive familial Mediterranean fever
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
familial Mediterranean fever
Inheritance: AR, SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet
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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072651207).

BP6

Variant 16-3248947-G-C is Benign according to our data. Variant chr16-3248947-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36499.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1318C>G	p.Gln440Glu	missense	Exon 4 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.685C>G	p.Gln229Glu	missense	Exon 3 of 9	NP_001185465.2	O15553-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1318C>G	p.Gln440Glu	missense	Exon 4 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.685C>G	p.Gln229Glu	missense	Exon 3 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.278-1701C>G		intron	N/A	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

543

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00119

AC:

299

AN:

251484

AF XY:

0.000927

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000373

AC:

545

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

231

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0108

AC:

361

AN:

33476

American (AMR)

AF:

0.00190

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1112004

Other (OTH)

AF:

0.000944

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00358

AC:

545

AN:

152328

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0110

AC:

458

AN:

41578

American (AMR)

AF:

0.00497

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000205

Hom.:

Bravo

AF:

0.00411

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00147

AC:

179

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial Mediterranean fever (3)

not provided (3)

Autoinflammatory syndrome (1)

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

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (1)

not specified (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.30

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

2.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.34

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.48

MVP

0.75

MPC

0.13

ClinPred

0.0097

GERP RS

3.4

Varity_R

0.16

gMVP

0.16

Mutation Taster

=69/31

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over