chr16-3243447-C-A

Position:

• chr16-3243447-C-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PS1 PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000243.3(MEFV):​c.2040G>T​(p.Met680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M680L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.167

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript NM_000243.3 (MEFV) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243449-T-G is described in Lovd as [Pathogenic].
• PP5: Variant 16-3243447-C-A is Pathogenic according to our data. Variant chr16-3243447-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32046145). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2040G>T	p.Met680Ile	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*244G>T		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.2040G>T	p.Met680Ile	missense_variant	10/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2016

The M680I mutation accounts for approximately 9% of identifiable MEFV mutations and has been detected in individuals from multiple ethnic backgrounds (Aksentijevich et al., 1999). In those individuals, the nucleotide substitutions observed at the cDNA level were c.2040 G>C or c.2040 G>A, rather than G>T as observed; however, the effect at the protein level is the same, resulting in a M680I mutation. -

Familial Mediterranean fever Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 680 of the MEFV protein (p.Met680Ile). 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: 23907647). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234365). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MEFV function (PMID: 21600797). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.00021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.58
DANN	Benign	0.58
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.33	T;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.60	N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.30
MutPred		0.82		Gain of catalytic residue at M680 (P = 0.0329);.;.;
MVP		0.54
MPC		0.13
ClinPred		0.80	D
GERP RS		-3.3
Varity_R		0.23
gMVP		0.18

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: rs28940580; hg19: chr16-3293447;