16-3247221-C-G

Variant names:

• chr16-3247221-C-G
• rs145637617
• NM_000243.3:c.1382G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000243.3(MEFV):​c.1382G>C​(p.Arg461Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R461Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial Mediterranean fever

  Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1382G>C	p.Arg461Pro	missense	Exon 5 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.749G>C	p.Arg250Pro	missense	Exon 4 of 9	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1382G>C	p.Arg461Pro	missense	Exon 5 of 10	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.749G>C	p.Arg250Pro	missense	Exon 4 of 9	ENSP00000438711.1
	MEFV	ENST00000539145.5	TSL:1	n.*15G>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000444471.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial Mediterranean fever Uncertain:1

Mar 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals affected with MEFV-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 461 of the MEFV protein (p.Arg461Pro).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.11
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.49		Loss of MoRF binding (P = 7e-04)
MVP		0.83
MPC		0.63
ClinPred		0.97	D
GERP RS		-1.8
Varity_R		0.70
gMVP		0.56

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

Other links and lift over

dbSNP: rs145637617; hg19: chr16-3297221;