NM_000243.3:c.414A>G

Variant names:

• chr16-3254654-T-C
• rs224224
• NM_000243.3:c.414A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):​c.414A>G​(p.Gly138Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,608,252 control chromosomes in the GnomAD database, including 174,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G138G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17589 hom., cov: 33)
  • Exomes 𝑓: 0.45 (156797 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17 O:1
• Conservation: PhyloP100: -0.557
• Publications: 32 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):

• autosomal recessive familial Mediterranean fever

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

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

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-3254654-T-C is Benign according to our data. Variant chr16-3254654-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.557 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.544 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.414A>G	p.Gly138Gly	synonymous	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+1657A>G		intron	N/A	NP_001185465.2	O15553-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.414A>G	p.Gly138Gly	synonymous	Exon 2 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.277+1657A>G		intron	N/A	ENSP00000438711.1	O15553-3
	MEFV	ENST00000570511.5	TSL:1	n.414A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71714 AN: 152054 Hom.: 17559 Cov.: 33

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.439 AC: 104601 AN: 238018 AF XY: 0.421

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.455 AC: 661840 AN: 1456084 Hom.: 156797 Cov.: 61 AF XY: 0.446 AC XY: 322865 AN XY: 724190

African (AFR) AF: 0.502 AC: 16765 AN: 33374

American (AMR) AF: 0.609 AC: 27068 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10500 AN: 26082

East Asian (EAS) AF: 0.147 AC: 5823 AN: 39642

South Asian (SAS) AF: 0.203 AC: 17515 AN: 86186

European-Finnish (FIN) AF: 0.505 AC: 25403 AN: 50298

Middle Eastern (MID) AF: 0.316 AC: 1816 AN: 5754

European-Non Finnish (NFE) AF: 0.478 AC: 530938 AN: 1110158

Other (OTH) AF: 0.432 AC: 26012 AN: 60152

GnomAD4 genome AF: 0.472 AC: 71803 AN: 152168 Hom.: 17589 Cov.: 33 AF XY: 0.468 AC XY: 34852 AN XY: 74404

African (AFR) AF: 0.506 AC: 21014 AN: 41544

American (AMR) AF: 0.554 AC: 8475 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1364 AN: 3468

East Asian (EAS) AF: 0.156 AC: 802 AN: 5150

South Asian (SAS) AF: 0.198 AC: 956 AN: 4828

European-Finnish (FIN) AF: 0.515 AC: 5465 AN: 10610

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32282 AN: 67954

Other (OTH) AF: 0.464 AC: 981 AN: 2112

Alfa AF: 0.414 Hom.: 2749

Bravo AF: 0.481

Asia WGS AF: 0.236 AC: 822 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Familial Mediterranean fever (5)
-	1	2	not provided (4)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.1
DANN	Benign	0.40
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs224224; hg19: chr16-3304654; COSMIC: COSV54819820;