rs104895100

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The ENST00000219596.6(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V487M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

MEFV
ENST00000219596.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.245

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=4, Likely_benign=3}. 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/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.1459G>C	p.Val487Leu	missense_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.826G>C	p.Val276Leu	missense_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.1459G>C	p.Val487Leu	missense_variant	5/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152196

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000331

AC XY:

AN XY:

135922

show subpopulations

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.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.00267

ESP6500AA

AF:

0.00797

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2022	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial Mediterranean fever

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 27, 2023	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 19, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Feb 27, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

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

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.5

N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over