NM_000243.3:c.442G>C

Variant names:

• chr16-3254626-C-G
• rs3743930
• NM_000243.3:c.442G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000243.3(MEFV):​c.442G>C​(p.Glu148Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,604,986 control chromosomes in the GnomAD database, including 5,896 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E148V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (459 hom., cov: 34)
  • Exomes 𝑓: 0.038 (5437 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:24 B:13 O:2
• Conservation: PhyloP100: 0.734
• Publications: 676 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055573583).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

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.442G>C	p.Glu148Gln	missense	Exon 2 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.277+1685G>C		intron	N/A	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.442G>C	p.Glu148Gln	missense	Exon 2 of 10	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.277+1685G>C		intron	N/A	ENSP00000438711.1
	MEFV	ENST00000570511.5	TSL:1	n.442G>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4998 AN: 152178 Hom.: 463 Cov.: 34

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0711 AC: 16654 AN: 234232 AF XY: 0.0810

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0377 AC: 54764 AN: 1452690 Hom.: 5437 Cov.: 63 AF XY: 0.0450 AC XY: 32507 AN XY: 722486

African (AFR) AF: 0.0171 AC: 568 AN: 33294

American (AMR) AF: 0.0133 AC: 586 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 1400 AN: 25984

East Asian (EAS) AF: 0.255 AC: 10078 AN: 39578

South Asian (SAS) AF: 0.280 AC: 24096 AN: 86008

European-Finnish (FIN) AF: 0.00188 AC: 91 AN: 48498

Middle Eastern (MID) AF: 0.0650 AC: 372 AN: 5720

European-Non Finnish (NFE) AF: 0.0131 AC: 14505 AN: 1109408

Other (OTH) AF: 0.0511 AC: 3068 AN: 60032

GnomAD4 genome AF: 0.0329 AC: 5006 AN: 152296 Hom.: 459 Cov.: 34 AF XY: 0.0380 AC XY: 2828 AN XY: 74454

African (AFR) AF: 0.0159 AC: 662 AN: 41580

American (AMR) AF: 0.0191 AC: 293 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3472

East Asian (EAS) AF: 0.280 AC: 1439 AN: 5148

South Asian (SAS) AF: 0.299 AC: 1442 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 861 AN: 68020

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0227 Hom.: 137

Bravo AF: 0.0282

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.0104 AC: 44

ESP6500EA AF: 0.0116 AC: 97

ExAC AF: 0.0716 AC: 8561

Asia WGS AF: 0.225 AC: 785 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	6	Familial Mediterranean fever (15)
2	7	3	not provided (12)
-	5	-	Familial Mediterranean fever, autosomal dominant (5)
-	-	2	Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (2)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MEFV-related disorder (1)
-	1	-	not specified (1)
-	1	-	See cases (1)
-	1	-	Systemic lupus erythematosus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.73
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.13
MPC		0.53
ClinPred		0.012	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.51
Mutation Taster		=95/5	disease causing (ClinVar)

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: rs3743930; hg19: chr16-3304626; COSMIC: COSV54822534;