Genetic Variant MEFV:p.Lys695Arg (chr16-3243403-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM5PP5BP4BS2

The NM_000243.3(MEFV):c.2084A>G(p.Lys695Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,186 control chromosomes in the GnomAD database, including 54 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. K695N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0049 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 48 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17U:22B:1O:3

Conservation

PhyloP100: 0.429

Publications

194 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000243.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3243402-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97490.

PP5

Variant 16-3243403-T-C is Pathogenic according to our data. Variant chr16-3243403-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2547.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049732625). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAd4 at 6 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.2084A>G	p.Lys695Arg	missense	Exon 10 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.*288A>G		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.2084A>G	p.Lys695Arg	missense	Exon 10 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.*288A>G		3_prime_UTR	Exon 9 of 9	ENSP00000438711.1	O15553-3
MEFV	ENST00000539145.5	TSL:1	n.*717A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes

AF:

0.00488

AC:

743

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00716

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00524

AC:

1319

AN:

251482

AF XY:

0.00499

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00913

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0163

Gnomad NFE exome

AF:

0.00680

Gnomad OTH exome

AF:

0.00668

GnomAD4 exome

AF:

0.00386

AC:

5641

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

2890

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

281

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0169

AC:

901

AN:

53404

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00371

AC:

4123

AN:

1112012

Other (OTH)

AF:

0.00391

AC:

236

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

400

800

1201

1601

2001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00488

AC:

743

AN:

152308

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41556

American (AMR)

AF:

0.00372

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0129

AC:

137

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00716

AC:

487

AN:

68020

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

118

157

196

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:

0.00589

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (16)

Familial Mediterranean fever (13)

Familial Mediterranean fever, autosomal dominant (2)

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (2)

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (2)

not specified (2)

Autoinflammatory syndrome (1)

Cachexia;C0031117:Peripheral neuropathy;C0039070:Syncope;C0042109:Urticaria;C0239181:Intermittent diarrhea;C0262444:Abnormality of the dentition (1)

Heart, malformation of;C1565489:Renal insufficiency;C4049796:Abnormal cardiovascular system morphology (1)

Hypercholesterolemia, familial, 1 (1)

Inborn genetic diseases (1)

MEFV-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.34

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PhyloP100

0.43

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.95

REVEL

Uncertain

0.35

Sift

Benign

0.13

Sift4G

Benign

0.15

Polyphen

0.94

Vest4

0.21

MVP

0.71

MPC

0.17

ClinPred

0.018

GERP RS

0.96

Varity_R

0.11

gMVP

0.16

Mutation Taster

=21/79

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