rs104895179

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000243.3(MEFV):c.586G>T(p.Gly196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,587,236 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G196R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 11 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6O:1

Conservation

PhyloP100: -0.403

Publications

12 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=0.0047331452).

BP6

Variant 16-3254482-C-A is Benign according to our data. Variant chr16-3254482-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97532.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000541 (776/1434888) while in subpopulation AFR AF = 0.0188 (616/32682). AF 95% confidence interval is 0.0176. There are 11 homozygotes in GnomAdExome4. There are 328 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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.586G>T	p.Gly196Trp	missense	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+1829G>T		intron	N/A	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.586G>T	p.Gly196Trp	missense	Exon 2 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.277+1829G>T		intron	N/A	ENSP00000438711.1	O15553-3
MEFV	ENST00000570511.5	TSL:1	n.586G>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes

AF:

0.00444

AC:

676

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00122

AC:

248

AN:

203408

AF XY:

0.000848

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000485

Gnomad NFE exome

AF:

0.0000457

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000541

AC:

776

AN:

1434888

Hom.:

Cov.:

AF XY:

0.000460

AC XY:

328

AN XY:

712366

show subpopulations

African (AFR)

AF:

0.0188

AC:

616

AN:

32682

American (AMR)

AF:

0.000987

AC:

AN:

40540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

39224

South Asian (SAS)

AF:

0.0000706

AC:

AN:

84960

European-Finnish (FIN)

AF:

0.000550

AC:

AN:

47238

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

4800

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

1100798

Other (OTH)

AF:

0.00105

AC:

AN:

59148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00444

AC:

676

AN:

152348

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

311

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0151

AC:

627

AN:

41588

American (AMR)

AF:

0.00222

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68014

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

137

171

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:

0.00165

Hom.:

Bravo

AF:

0.00550

ESP6500AA

AF:

0.00960

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00138

AC:

158

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial Mediterranean fever (5)

not provided (3)

Autoinflammatory syndrome (1)

Familial Mediterranean fever, autosomal dominant (1)

MEFV-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.35

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

PhyloP100

-0.40

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.46

Vest4

0.74

MVP

0.33

MPC

0.16

ClinPred

0.014

GERP RS

-2.3

Varity_R

0.070

gMVP

0.26

Mutation Taster

=65/35

polymorphism

(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