rs104895137

Variant names:

• chr16-3249421-G-A
• rs104895137
• NM_000243.3:c.1260+10C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3249421-G-A
• chr16-3249421-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5 O:1
• Conservation: PhyloP100: -0.809
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 VariationId is 36498.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1260+10C>T		intron_variant	Intron 3 of 9	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.627+10C>T		intron_variant	Intron 2 of 8		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1260+10C>T		intron_variant	Intron 3 of 9	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152240 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000570 AC: 141 AN: 247282 AF XY: 0.000522

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.000738 AC: 33 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52154

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5688

European-Non Finnish (NFE) AF: 0.0000739 AC: 82 AN: 1109372

Other (OTH) AF: 0.000879 AC: 53 AN: 60278

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74506

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Benign:2 Other:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 13, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not specified Benign:2

May 14, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 16, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV 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

Aug 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Sep 30, 2020

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV 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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.29
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs104895137; hg19: chr16-3299421;