NM_000243.3:c.1129C>G

Variant names:

• chr16-3249562-G-C
• rs896909303
• NM_000243.3:c.1129C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000243.3(MEFV):​c.1129C>G​(p.Arg377Gly) 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. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.105
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3427591).

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.1129C>G	p.Arg377Gly	missense	Exon 3 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.496C>G	p.Arg166Gly	missense	Exon 2 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.1129C>G	p.Arg377Gly	missense	Exon 3 of 10	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.496C>G	p.Arg166Gly	missense	Exon 2 of 9	ENSP00000438711.1
	MEFV	ENST00000539145.5	TSL:1	n.278-2316C>G		intron	N/A	ENSP00000444471.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Familial Mediterranean fever (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.10
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.041	D
Polyphen		0.72	P
Vest4		0.35
MutPred		0.44		Gain of ubiquitination at K376 (P = 0.0304)
MVP		0.71
MPC		0.59
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.28
gMVP		0.28

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: rs896909303; hg19: chr16-3299562;