NM_000243.3:c.1772T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000243.3(MEFV):c.1772T>C(p.Ile591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,932 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. I591M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 17 hom., cov: 32)

Exomes 𝑓: 0.015 ( 186 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11O:1

Conservation

PhyloP100: -1.01

Publications

69 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003907919).

BP6

Variant 16-3243880-A-G is Benign according to our data. Variant chr16-3243880-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36506.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00985 (1500/152258) while in subpopulation NFE AF = 0.016 (1090/68018). AF 95% confidence interval is 0.0152. There are 17 homozygotes in GnomAd4. There are 713 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 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.1772T>C	p.Ile591Thr	missense	Exon 9 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.1314T>C	p.Asp438Asp	synonymous	Exon 8 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.1772T>C	p.Ile591Thr	missense	Exon 9 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.1314T>C	p.Asp438Asp	synonymous	Exon 8 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.*405T>C		non_coding_transcript_exon	Exon 6 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.00987

AC:

1501

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.0107

AC:

2682

AN:

251076

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.0150

AC:

21896

AN:

1461674

Hom.:

186

Cov.:

AF XY:

0.0144

AC XY:

10476

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33480

American (AMR)

AF:

0.00358

AC:

160

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00457

AC:

394

AN:

86250

European-Finnish (FIN)

AF:

0.0209

AC:

1114

AN:

53244

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0173

AC:

19222

AN:

1111986

Other (OTH)

AF:

0.0134

AC:

810

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1235

2470

3705

4940

6175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.00985

AC:

1500

AN:

152258

Hom.:

Cov.:

AF XY:

0.00958

AC XY:

713

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

41542

American (AMR)

AF:

0.00471

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5178

South Asian (SAS)

AF:

0.00373

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0160

AC:

1090

AN:

68018

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

151

226

302

377

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:

0.0136

Hom.:

Bravo

AF:

0.00876

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0152

AC:

131

ExAC

AF:

0.0102

AC:

1240

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Familial Mediterranean fever (4)

not specified (2)

Acute febrile neutrophilic dermatosis (1)

Autoinflammatory syndrome (1)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.10

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.29

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

PhyloP100

-1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.010

REVEL

Benign

0.17

Sift

Benign

0.42

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.17

MPC

0.15

ClinPred

0.00067

GERP RS

-7.4

Varity_R

0.067

gMVP

0.12

Mutation Taster

=56/44

polymorphism

(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