rs104895137

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000243.3(MEFV):​c.1260+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,609,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

MEFV
NM_000243.3 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: -0.809
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 16-3249421-G-A is Benign according to our data. Variant chr16-3249421-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=4, not_provided=1, Benign=3}. Variant chr16-3249421-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MEFVNM_000243.3 linkuse as main transcriptc.1260+10C>T intron_variant ENST00000219596.6 NP_000234.1 O15553-2
MEFVNM_001198536.2 linkuse as main transcriptc.627+10C>T intron_variant NP_001185465.2 O15553-3D2DTW2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MEFVENST00000219596.6 linkuse as main transcriptc.1260+10C>T intron_variant 1 NM_000243.3 ENSP00000219596.1 O15553-2

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.00720
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000570
AC:
141
AN:
247282
Hom.:
1
AF XY:
0.000522
AC XY:
70
AN XY:
134062
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000695
Gnomad ASJ exome
AF:
0.00932
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000144
Gnomad OTH exome
AF:
0.00132
GnomAD4 exome
AF:
0.000308
AC:
449
AN:
1457596
Hom.:
1
Cov.:
31
AF XY:
0.000307
AC XY:
223
AN XY:
725226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000738
Gnomad4 ASJ exome
AF:
0.0107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000739
Gnomad4 OTH exome
AF:
0.000879
GnomAD4 genome
AF:
0.000341
AC:
52
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.000228
AC XY:
17
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00720
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00161
Hom.:
0
Bravo
AF:
0.000453

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial Mediterranean fever Uncertain:1Benign:2Other:1
not provided, no classification providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2024- -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.May 13, 2020- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 14, 2019- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 16, 2022Variant summary: MEFV c.1260+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 247282 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00057 vs 0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1260+10C>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign n=2, like benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. -
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021MEFV NM_000243.2 exon 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenAug 09, 2021- -
Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoSep 30, 2020MEFV NM_000243.2 exon 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
4.5
DANN
Benign
0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104895137; hg19: chr16-3299421; API