rs104895105

chr16-3247171-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000243.3(MEFV):c.1432C>T(p.His478Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/21 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: not found (cov: 33)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2 O:1
• Conservation: PhyloP100: -0.0980

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-3247171-G-A is Benign according to our data. Variant chr16-3247171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2557.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1432C>T	p.His478Tyr	missense_variant	5/10	ENST00000219596.6
MEFV	NM_001198536.2	c.799C>T	p.His267Tyr	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1432C>T	p.His478Tyr	missense_variant	5/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:3 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2557). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 14679589). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 478 of the MEFV protein (p.His478Tyr). -

Familial Mediterranean fever, autosomal dominant Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	Reported in published literature in individuals from a family with an autosomal dominant periodic inflammatory disorder with renal AA amyloidosis and was found to exclusively co-segregate with the disease in all individuals tested (Aldea et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19479870, 22614345, 18328141, 29260407, 23844200, 23031807, 27225717, 15024744, 14679589) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MEFV: PM2, PP1:Moderate, PP4, BP4 -

Acute febrile neutrophilic dermatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	2.1
Dann	Benign	0.78
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N;.;.;.
MutationTaster	Benign	0.000027	A;A;A;A
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.79	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.11	T;T;D;T
Polyphen		0.75	P;.;.;.
Vest4		0.17
MutPred		0.76		Gain of phosphorylation at H478 (P = 0.054);.;.;.;
MVP		0.62
MPC		0.21
ClinPred		0.13	T
GERP RS		2.2
Varity_R		0.096
gMVP		0.076

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: rs104895105; hg19: chr16-3297171;