rs76464258

Variant names:

• chr16-3247100-G-A
• rs76464258
• NM_000243.3:c.1503C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000243.3(MEFV):​c.1503C>T​(p.Arg501Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,614,126 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (270 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• Conservation: PhyloP100: -4.40
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-3247100-G-A is Benign according to our data. Variant chr16-3247100-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36501.
• BP7: Synonymous conserved (PhyloP=-4.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0936 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.1503C>T	p.Arg501Arg	synonymous	Exon 5 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.870C>T	p.Arg290Arg	synonymous	Exon 4 of 9	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.1503C>T	p.Arg501Arg	synonymous	Exon 5 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.870C>T	p.Arg290Arg	synonymous	Exon 4 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*136C>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes AF: 0.00867 AC: 1319 AN: 152166 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0125 AC: 3139 AN: 251492 AF XY: 0.0127

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00661 AC: 9662 AN: 1461842 Hom.: 270 Cov.: 66 AF XY: 0.00683 AC XY: 4970 AN XY: 727218

African (AFR) AF: 0.00352 AC: 118 AN: 33480

American (AMR) AF: 0.00387 AC: 173 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 468 AN: 26136

East Asian (EAS) AF: 0.0877 AC: 3481 AN: 39698

South Asian (SAS) AF: 0.0150 AC: 1296 AN: 86246

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53416

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.00285 AC: 3172 AN: 1111990

Other (OTH) AF: 0.0147 AC: 889 AN: 60396

GnomAD4 genome AF: 0.00865 AC: 1318 AN: 152284 Hom.: 30 Cov.: 33 AF XY: 0.00935 AC XY: 696 AN XY: 74462

African (AFR) AF: 0.00431 AC: 179 AN: 41570

American (AMR) AF: 0.0117 AC: 179 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.101 AC: 522 AN: 5182

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68036

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00466 Hom.: 3

Bravo AF: 0.00941

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Familial Mediterranean fever (6)
-	-	3	not provided (3)
-	-	1	Acute febrile neutrophilic dermatosis (1)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.43
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76464258; hg19: chr16-3297100; COSMIC: COSV54823871;