NM_000243.3:c.2177T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3PP5_Very_StrongBP4BS2_Supporting

The NM_000243.3(MEFV):c.2177T>C(p.Val726Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,072 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000629038: Experimental studies have shown that this missense change affects MEFV function (PMID:21600797)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V726I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 23 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:53O:2

Conservation

PhyloP100: -0.165

Publications

583 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: Pathogenic. The variant received 10 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000629038: Experimental studies have shown that this missense change affects MEFV function (PMID: 21600797).; SCV000711424: "In vitro functional studies of the protein domain containing p.Val726Ala variant report an impact to protein binding." PMID:21600797; SCV001142454: Functional studies demonstrate that p.Val726Ala has decreased protein binding activity(PMID: 16785446).; SCV001469021: There is evidence that p.Val726Ala leads to decreased binding of the B30.2 domain of human pyrin to caspase-13 in vitro.; SCV005398586: "This variant has moderate functional evidence supporting abnormal protein function. In transfected cells, the mutant protein had decreased binding to caspase-1 (PMID: 16785446). This is consistent with the functional study using knock-in mice which showed gain of caspase-1 activation (PMID: 21600797)."; SCV000279062: Multiple published functional and FMF-knock-in mice studies demonstrate that this variant decreases protein binding activity (Chae et al., 2006) and shows decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, leading to constitutive activation of the pyrin inflammosome (Park YH et al., 2016); homozygosity for this MEFV variant in knock-in mice produced the most severe inflammation from all tested MEFV variants (Park YH et al., 2016).; SCV002318773: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797).; SCV005366093: "In vivo and in vitro experimental studies suggest this variant impacts protein function (Chae et al. 2011. PubMed ID: 21600797; Honda et al. 2021. PubMed ID: 33733382)."

PP5

Variant 16-3243310-A-G is Pathogenic according to our data. Variant chr16-3243310-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.09626025). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAd4 at 3 AR,SD,AD 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.2177T>C	p.Val726Ala	missense	Exon 10 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.*381T>C		3_prime_UTR	Exon 9 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.2177T>C	p.Val726Ala	missense	Exon 10 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.*381T>C		3_prime_UTR	Exon 9 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.*810T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000721

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00217

AC:

545

AN:

251486

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.0398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000932

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00130

AC:

1896

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

963

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

1013

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000469

AC:

521

AN:

1112012

Other (OTH)

AF:

0.00435

AC:

263

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00144

AC:

219

AN:

152184

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41528

American (AMR)

AF:

0.000458

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

68000

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

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:

0.00201

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00185

AC:

224

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial Mediterranean fever (25)

not provided (14)

Familial Mediterranean fever, autosomal dominant (6)

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (3)

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (3)

MEFV-related disorder (2)

Autoinflammatory syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.17

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.29

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.48

M_CAP

Benign

0.020

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-2.2

PhyloP100

-0.17

PrimateAI

Benign

0.24

PROVEAN

Benign

1.9

REVEL

Uncertain

0.35

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.26

MVP

0.53

MPC

0.14

ClinPred

0.023

GERP RS

-0.52

Varity_R

0.089

gMVP

0.13

Mutation Taster

=45/55

disease causing (ClinVar)

(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