rs75977701

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP6BS1BS2_Supporting

The NM_000243.3(MEFV):c.910G>A(p.Gly304Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,990 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 32 hom. )

Consequence

MEFV
NM_000243.3 missense, splice_region

Scores

Splicing: ADA: 0.9978

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6O:1

Conservation

PhyloP100: 0.0780

Publications

53 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: Likely_benign. The variant received -5 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 16-3254158-C-T is Benign according to our data. Variant chr16-3254158-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36513.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0034 (518/152332) while in subpopulation EAS AF = 0.0224 (116/5180). AF 95% confidence interval is 0.0191. There are 3 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,SD 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.910G>A	p.Gly304Arg	missense splice_region	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+2153G>A		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.910G>A	p.Gly304Arg	missense splice_region	Exon 2 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.277+2153G>A		intron	N/A	ENSP00000438711.1	O15553-3
MEFV	ENST00000570511.5	TSL:1	n.910G>A		splice_region non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes

AF:

0.00340

AC:

518

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00458

AC:

1144

AN:

249962

AF XY:

0.00430

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.000934

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00209

AC:

3058

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1534

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26136

East Asian (EAS)

AF:

0.0222

AC:

880

AN:

39700

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86242

European-Finnish (FIN)

AF:

0.0263

AC:

1403

AN:

53298

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000289

AC:

321

AN:

1111930

Other (OTH)

AF:

0.00340

AC:

205

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

171

342

514

685

856

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:

0.00340

AC:

518

AN:

152332

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

338

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5180

South Asian (SAS)

AF:

0.00269

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0271

AC:

288

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00158

Hom.:

Bravo

AF:

0.00138

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Familial Mediterranean fever (4)

not specified (2)

Autoinflammatory syndrome (1)

MEFV-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00076

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

0.078

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

REVEL

Benign

0.055

Sift

Uncertain

0.0010

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.21

MutPred

0.24

Gain of solvent accessibility (P = 0.019)

MVP

0.51

MPC

0.14

ClinPred

0.0094

GERP RS

-1.4

Varity_R

0.16

gMVP

0.22

Mutation Taster

=95/5

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.71

Position offset: 0

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