rs104895100

Variant names:

• chr16-3247144-C-G
• rs104895100
• NM_000243.3:c.1459G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-3247144-C-G
• chr16-3247144-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000243.3(MEFV):​c.1459G>C​(p.Val487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,614,190 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: -0.245

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031388104).
• BP6: Variant 16-3247144-C-G is Benign according to our data. Variant chr16-3247144-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378132.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr16-3247144-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1459G>C	p.Val487Leu	missense_variant	Exon 5 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.826G>C	p.Val276Leu	missense_variant	Exon 4 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1459G>C	p.Val487Leu	missense_variant	Exon 5 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.000478

GnomAD3 exomes AF: 0.000612 AC: 154 AN: 251496 Hom.: 2 AF XY: 0.000331 AC XY: 45 AN XY: 135922

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461876 Hom.: 0 Cov.: 65 AF XY: 0.000161 AC XY: 117 AN XY: 727240

Gnomad4 AFR exome AF: 0.00732

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00197 AC XY: 147 AN XY: 74470

Gnomad4 AFR AF: 0.00786

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.00267

ESP6500AA AF: 0.00797 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000824 AC: 100

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

May 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.1459G>C; p.Val487Leu variant (rs104895100) has been reported in individuals affected with familial Mediterranean fever (see link to database, Gumus 2018, Moradian 2017), but was not determined to be causative and was classified as "unsolved" by an expert panel (Van Gijn 2018). The variant is reported in the ClinVar database (Variation ID: 378132) and is reported in the African population with an allele frequency of 0.76% (189/24,964 alleles including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.075). Although the population frequency of this variant is relatively high, the possibility of reduced penetrance or a mild effect cannot be excluded. Therefore, due to conflicting information and lack of functional data, the significance of this variant cannot be determined with certainty. References: Link to Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 Gumus E. The Frequency of MEFV Gene Mutations and Genotypes in Sanliurfa Province, South-Eastern Region of Turkey, after the Syrian Civil War by Using Next Generation Sequencing and Report of a Novel Exon 4 Mutation (I423T). J Clin Med. 2018 May 7;7(5):105. PMID: 29735907. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537. PMID: 29599418. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial Mediterranean fever Uncertain:1 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This MEFV missense variant has been reported in an individual suspected to have familial Mediterranean fever. The variant (rs104895100) is present in a large population dataset (gnomAD v3.1.2: 339/152196 total alleles; 0.223%; 3 homozygotes), and has been reported in ClinVar2 (Variation ID 378132). Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The valine residue at this position is evolutionarily conserved across very few of the species assessed, and most of the species have leucine at this position. We consider the clinical significance of c.1459G>C; p.Val487Leu in MEFV to be uncertain at this time. -

not specified Uncertain:1

Apr 19, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEFV c.1459G>C (p.Val487Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251496 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00061 vs 0.022), allowing no conclusion about variant significance. c.1459G>C has been reported in the literature in an individual (heterozygous) with clinically suspected Familial Mediterranean Fever (Gumus_2018). In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported classification and status of this variant as Unsolved (Van Gijn_2018). Recently however, Accetturo et al proposed a classification of likely benign (Accetturo _2019) based on a variant metapredictor tool REVEL (Rare Exome Variant Ensemble Learner) for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31411330, 29599418, 29735907, 29178647). ClinVar contains an entry for this variant (Variation ID: 378132). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Familial Mediterranean fever, autosomal dominant Uncertain:1

Feb 27, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This MEFV missense variant has been reported in an individual suspected to have familial Mediterranean fever. The variant (rs104895100) is present in a large population dataset (gnomAD v3.1.2: 339/152196 total alleles; 0.223%; 3 homozygotes), and has been reported in ClinVar2 (Variation ID 378132). Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The valine residue at this position is evolutionarily conserved across very few of the species assessed, and most of the species have leucine at this position. We consider the clinical significance of c.1459G>C; p.Val487Leu in MEFV to be uncertain at this time. -

Autoinflammatory syndrome Benign:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.35
DANN	Benign	0.12
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.5	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.051
MutPred		0.46		Loss of MoRF binding (P = 0.336);.;.;.;
MVP		0.38
MPC		0.11
ClinPred		0.0087	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.12

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

Other links and lift over

dbSNP: rs104895100; hg19: chr16-3297144;