rs104895105

Variant names:

• chr16-3247171-G-A
• rs104895105
• NM_000243.3:c.1432C>T

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: {Likely_benign=2, Uncertain_significance=5, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1432C>T	p.His478Tyr	missense_variant	Exon 5 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.799C>T	p.His267Tyr	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.1432C>T	p.His478Tyr	missense_variant	Exon 5 of 10	1	NM_000243.3	ENSP00000219596.1

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

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 14679589). ClinVar contains an entry for this variant (Variation ID: 2557). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

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

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 08, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jun 21, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV: PM2, PP1:Moderate, PP4, BP4 -

Acute febrile neutrophilic dermatosis Benign:1

Feb 08, 2023

Genome-Nilou Lab

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	0.098
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;.;.;.
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;