chr16-3254529-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000243.3(MEFV):c.539C>T(p.Pro180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,555,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. P180Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -0.0530

Publications

5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.062740624).

BP6

Variant 16-3254529-G-A is Benign according to our data. Variant chr16-3254529-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527803.

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.539C>T	p.Pro180Leu	missense	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+1782C>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.539C>T	p.Pro180Leu	missense	Exon 2 of 10	ENSP00000219596.1	O15553-2
MEFV	ENST00000541159.5	TSL:1	c.277+1782C>T		intron	N/A	ENSP00000438711.1	O15553-3
MEFV	ENST00000570511.5	TSL:1	n.539C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000640

AC:

AN:

156302

AF XY:

0.0000116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1402860

Hom.:

Cov.:

AF XY:

0.00000720

AC XY:

AN XY:

693966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32074

American (AMR)

AF:

0.00

AC:

AN:

36530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

36982

South Asian (SAS)

AF:

0.00

AC:

AN:

81800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4358

European-Non Finnish (NFE)

AF:

0.0000184

AC:

AN:

1085904

Other (OTH)

AF:

0.0000172

AC:

AN:

58128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial Mediterranean fever (3)

Acute febrile neutrophilic dermatosis (1)

Familial Mediterranean fever, autosomal dominant (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.96

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.25

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.48

M_CAP

Benign

0.018

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

PhyloP100

-0.053

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.060

REVEL

Benign

0.079

Sift

Benign

0.14

Sift4G

Benign

0.39

Polyphen

0.0070

Vest4

0.16

MutPred

0.24

Gain of MoRF binding (P = 0.0379)

MVP

0.43

MPC

0.12

ClinPred

0.046

GERP RS

-4.3

Varity_R

0.025

gMVP

0.14

Mutation Taster

=60/40

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