rs11466023

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000243.3(MEFV):c.1105C>T(p.Pro369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,188 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. P369T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 31 hom., cov: 33)

Exomes 𝑓: 0.010 ( 215 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:5O:1

Conservation

PhyloP100: 1.69

Publications

292 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018258095).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0122 (1861/152322) while in subpopulation EAS AF = 0.0729 (377/5168). AF 95% confidence interval is 0.0669. There are 31 homozygotes in GnomAd4. There are 988 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 31 AR,AD,SD 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.1105C>T	p.Pro369Ser	missense	Exon 3 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.472C>T	p.Pro158Ser	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.1105C>T	p.Pro369Ser	missense	Exon 3 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.472C>T	p.Pro158Ser	missense	Exon 2 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.278-2340C>T		intron	N/A	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1861

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.0734

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00944

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0146

AC:

3651

AN:

250836

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.0700

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.00814

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0103

AC:

15105

AN:

1461866

Hom.:

215

Cov.:

AF XY:

0.0105

AC XY:

7651

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.00568

AC:

254

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

789

AN:

26136

East Asian (EAS)

AF:

0.0621

AC:

2467

AN:

39698

South Asian (SAS)

AF:

0.0156

AC:

1347

AN:

86258

European-Finnish (FIN)

AF:

0.0140

AC:

746

AN:

53408

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00739

AC:

8216

AN:

1112004

Other (OTH)

AF:

0.0178

AC:

1074

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

917

1834

2750

3667

4584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.0122

AC:

1861

AN:

152322

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

988

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00462

AC:

192

AN:

41590

American (AMR)

AF:

0.0161

AC:

246

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3470

East Asian (EAS)

AF:

0.0729

AC:

377

AN:

5168

South Asian (SAS)

AF:

0.0180

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0121

AC:

129

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00944

AC:

642

AN:

68026

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0109

Hom.:

Bravo

AF:

0.0114

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.0142

AC:

1720

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

EpiCase

AF:

0.00938

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 (2)

Autoinflammatory syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

1.7

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.24

Sift

Benign

0.036

Sift4G

Benign

0.080

Polyphen

0.96

Vest4

0.14

MPC

0.46

ClinPred

0.035

GERP RS

1.1

Varity_R

0.088

gMVP

0.25

Mutation Taster

=97/3

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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