ENST00000541159.5:c.1306G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000541159.5(MEFV):c.1306G>A(p.Gly436Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,612,752 control chromosomes in the GnomAD database, including 153,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 12998 hom., cov: 31)

Exomes 𝑓: 0.43 ( 140598 hom. )

Consequence

MEFV
ENST00000541159.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.206

Publications

41 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):

familial Mediterranean fever
Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
autosomal recessive familial Mediterranean fever
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.046295E-4).

BP6

Variant 16-3243888-C-T is Benign according to our data. Variant chr16-3243888-C-T is described in ClinVar as Benign. ClinVar VariationId is 36505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541159.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1764G>A	p.Pro588Pro	synonymous	Exon 9 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.1306G>A	p.Gly436Arg	missense	Exon 8 of 9	NP_001185465.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MEFV	ENST00000541159.5	TSL:1	c.1306G>A	p.Gly436Arg	missense	Exon 8 of 9	ENSP00000438711.1
MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1764G>A	p.Pro588Pro	synonymous	Exon 9 of 10	ENSP00000219596.1
MEFV	ENST00000539145.5	TSL:1	n.*397G>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000444471.1

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62069

AN:

151778

Hom.:

12999

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.599

Gnomad AMR

AF:

0.375

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.442

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.461

Gnomad OTH

AF:

0.426

GnomAD2 exomes

AF:

0.392

AC:

98072

AN:

250496

AF XY:

0.396

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.444

Gnomad EAS exome

AF:

0.378

Gnomad FIN exome

AF:

0.429

Gnomad NFE exome

AF:

0.459

Gnomad OTH exome

AF:

0.431

GnomAD4 exome

AF:

0.434

AC:

634285

AN:

1460856

Hom.:

140598

Cov.:

AF XY:

0.432

AC XY:

313647

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.333

AC:

11130

AN:

33468

American (AMR)

AF:

0.272

AC:

12164

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.440

AC:

11508

AN:

26136

East Asian (EAS)

AF:

0.386

AC:

15331

AN:

39696

South Asian (SAS)

AF:

0.286

AC:

24670

AN:

86230

European-Finnish (FIN)

AF:

0.436

AC:

23214

AN:

53230

Middle Eastern (MID)

AF:

0.442

AC:

2548

AN:

5768

European-Non Finnish (NFE)

AF:

0.457

AC:

507896

AN:

1111288

Other (OTH)

AF:

0.428

AC:

25824

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

21658

43316

64973

86631

108289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15010

30020

45030

60040

75050

<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:

0.409

AC:

62086

AN:

151896

Hom.:

12998

Cov.:

AF XY:

0.404

AC XY:

30014

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.338

AC:

13983

AN:

41414

American (AMR)

AF:

0.375

AC:

5723

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

1511

AN:

3468

East Asian (EAS)

AF:

0.388

AC:

1995

AN:

5148

South Asian (SAS)

AF:

0.272

AC:

1313

AN:

4824

European-Finnish (FIN)

AF:

0.442

AC:

4652

AN:

10520

Middle Eastern (MID)

AF:

0.497

AC:

145

AN:

292

European-Non Finnish (NFE)

AF:

0.461

AC:

31326

AN:

67952

Other (OTH)

AF:

0.424

AC:

893

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1894

3788

5683

7577

9471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.438

Hom.:

40777

Bravo

AF:

0.400

TwinsUK

AF:

0.456

AC:

1691

ALSPAC

AF:

0.458

AC:

1767

ESP6500AA

AF:

0.342

AC:

1501

ESP6500EA

AF:

0.465

AC:

4003

ExAC

AF:

0.394

AC:

47781

Asia WGS

AF:

0.307

AC:

1068

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Benign:5

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

Jan 14, 2015

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 19, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MEFV: BP7, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:3

Dec 14, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial Mediterranean fever, autosomal dominant

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.28

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.27

MetaRNN

Benign

0.00060

MetaSVM

Benign

-0.95

PhyloP100

-0.21

PROVEAN

Benign

1.7

REVEL

Benign

0.044

Sift

Benign

1.0

Sift4G

Benign

0.76

Vest4

0.16

MutPred

0.30

Gain of MoRF binding (P = 0.0046)

ClinPred

0.0021

GERP RS

-0.23

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over