chr16-3254661-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000243.3(MEFV):​c.407G>A​(p.Gly136Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000507 in 1,458,506 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.0430

Publications

3 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6
Variant 16-3254661-C-T is Benign according to our data. Variant chr16-3254661-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234351.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEFVNM_000243.3 linkc.407G>A p.Gly136Glu missense_variant Exon 2 of 10 ENST00000219596.6 NP_000234.1 O15553-2
MEFVNM_001198536.2 linkc.277+1650G>A intron_variant Intron 1 of 8 NP_001185465.2 O15553-3D2DTW2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEFVENST00000219596.6 linkc.407G>A p.Gly136Glu missense_variant Exon 2 of 10 1 NM_000243.3 ENSP00000219596.1 O15553-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD2 exomes
AF:
0.0000249
AC:
6
AN:
240892
AF XY:
0.0000302
show subpopulations
Gnomad AFR exome
AF:
0.0000684
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:
0.0000466
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000507
AC:
74
AN:
1458506
Hom.:
0
Cov.:
64
AF XY:
0.0000510
AC XY:
37
AN XY:
725584
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33416
American (AMR)
AF:
0.00
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50998
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.0000639
AC:
71
AN:
1111338
Other (OTH)
AF:
0.0000332
AC:
2
AN:
60304
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
Cov.:
34
Alfa
AF:
0.0000314
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial Mediterranean fever Uncertain:3
May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 20, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine with glutamic acid at codon 136 of the MEFV protein (p.Gly136Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with familial mediterranean fever (PMID: 23862117). ClinVar contains an entry for this variant (Variation ID: 234351). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 08, 2023
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Jul 30, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

not provided Uncertain:1
Jul 23, 2015
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The G136E variant has been reported previously as a novel variant identified in an individual diagnosed with familial Mediterranean fever syndrome (Mohammadnejad et al. 2013). The G136E variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G136E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (E128V, G138A, S141L, R143P) have been reported in the Human Gene Mutation Database in association with MEFV-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

Acute febrile neutrophilic dermatosis Benign:1
Feb 08, 2023
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial Mediterranean fever, autosomal dominant Benign:1
Feb 08, 2023
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
15
DANN
Benign
0.96
DEOGEN2
Benign
0.37
T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.56
T
M_CAP
Uncertain
0.090
D
MetaRNN
Uncertain
0.64
D
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L
PhyloP100
0.043
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.98
N
REVEL
Benign
0.28
Sift
Uncertain
0.024
D
Sift4G
Uncertain
0.047
D
Polyphen
0.92
P
Vest4
0.78
MutPred
0.20
Loss of catalytic residue at G136 (P = 0.0056);
MVP
0.78
MPC
0.52
ClinPred
0.075
T
GERP RS
1.2
Varity_R
0.059
gMVP
0.30
Mutation Taster
=43/57
disease causing

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

Other links and lift over

dbSNP: rs876660989; hg19: chr16-3304661; API