16-3249468-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000243.3(MEFV):c.1223G>A(p.Arg408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,052 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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. R408L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 165 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:6O:1

Conservation

PhyloP100: -0.571

Publications

158 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: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0115 (1752/152326) while in subpopulation EAS AF = 0.055 (285/5182). AF 95% confidence interval is 0.0498. There are 28 homozygotes in GnomAd4. There are 928 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,SD,AD gene

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.1223G>A	p.Arg408Gln	missense	Exon 3 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.590G>A	p.Arg197Gln	missense	Exon 2 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.1223G>A	p.Arg408Gln	missense	Exon 3 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.590G>A	p.Arg197Gln	missense	Exon 2 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.278-2222G>A		intron	N/A	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1752

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00475

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00930

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0132

AC:

3314

AN:

250794

AF XY:

0.0138

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.0530

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00813

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00991

AC:

14481

AN:

1461726

Hom.:

165

Cov.:

AF XY:

0.0101

AC XY:

7344

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.00561

AC:

251

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0301

AC:

787

AN:

26132

East Asian (EAS)

AF:

0.0497

AC:

1975

AN:

39700

South Asian (SAS)

AF:

0.0152

AC:

1311

AN:

86248

European-Finnish (FIN)

AF:

0.0140

AC:

745

AN:

53288

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00739

AC:

8223

AN:

1112000

Other (OTH)

AF:

0.0162

AC:

976

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

832

1664

2496

3328

4160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.0115

AC:

1752

AN:

152326

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

928

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00469

AC:

195

AN:

41574

American (AMR)

AF:

0.0157

AC:

240

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3472

East Asian (EAS)

AF:

0.0550

AC:

285

AN:

5182

South Asian (SAS)

AF:

0.0176

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0121

AC:

128

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00931

AC:

633

AN:

68024

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

176

263

351

439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00364

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.0128

AC:

1554

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.00925

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Familial Mediterranean fever (7)

not specified (3)

Autoinflammatory syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.23

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

PhyloP100

-0.57

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.0

REVEL

Benign

0.035

Sift

Benign

0.23

Sift4G

Benign

0.27

Polyphen

0.26

Vest4

0.063

MPC

0.14

ClinPred

0.0014

GERP RS

-2.5

Varity_R

0.038

gMVP

0.15

Mutation Taster

=98/2

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -1

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