rs224208

Positions:

• chr16-3247181-C-G
• chr16-3247181-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000243.3(MEFV):​c.1422G>C​(p.Glu474Asp) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.956

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17416161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1422G>C	p.Glu474Asp	missense_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.789G>C	p.Glu263Asp	missense_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1422G>C	p.Glu474Asp	missense_variant	5/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;D;N
REVEL	Benign	0.26
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.98	D;.;.;.
Vest4		0.15
MutPred		0.28		Gain of phosphorylation at Y470 (P = 0.1249);.;.;.;
MVP		0.85
MPC		0.48
ClinPred		0.56	D
GERP RS		2.3
Varity_R		0.26
gMVP		0.24

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: rs224208; hg19: chr16-3297181;