rs224207

Variant names:

• chr16-3247175-T-C
• rs224207
• NM_000243.3:c.1428A>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.1428A>G​(p.Gln476Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,124 control chromosomes in the GnomAD database, including 262,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26194 hom., cov: 32)
  • Exomes 𝑓: 0.56 (236098 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.03
• 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=-0.81).
• BP6: Variant 16-3247175-T-C is Benign according to our data. Variant chr16-3247175-T-C is described in ClinVar as Benign. ClinVar VariationId is 255615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.707 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.1428A>G	p.Gln476Gln	synonymous	Exon 5 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.795A>G	p.Gln265Gln	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.1428A>G	p.Gln476Gln	synonymous	Exon 5 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.795A>G	p.Gln265Gln	synonymous	Exon 4 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*61A>G		non_coding_transcript_exon	Exon 2 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88598 AN: 151460 Hom.: 26154 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.608 AC: 152877 AN: 251442 AF XY: 0.603

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.658

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.565 AC: 825635 AN: 1461544 Hom.: 236098 Cov.: 63 AF XY: 0.568 AC XY: 412707 AN XY: 727090

African (AFR) AF: 0.647 AC: 21675 AN: 33478

American (AMR) AF: 0.725 AC: 32435 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14383 AN: 26132

East Asian (EAS) AF: 0.639 AC: 25369 AN: 39696

South Asian (SAS) AF: 0.714 AC: 61554 AN: 86248

European-Finnish (FIN) AF: 0.562 AC: 30042 AN: 53412

Middle Eastern (MID) AF: 0.554 AC: 3195 AN: 5764

European-Non Finnish (NFE) AF: 0.542 AC: 602514 AN: 1111702

Other (OTH) AF: 0.571 AC: 34468 AN: 60390

GnomAD4 genome AF: 0.585 AC: 88697 AN: 151580 Hom.: 26194 Cov.: 32 AF XY: 0.589 AC XY: 43660 AN XY: 74064

African (AFR) AF: 0.643 AC: 26545 AN: 41292

American (AMR) AF: 0.622 AC: 9476 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1916 AN: 3466

East Asian (EAS) AF: 0.642 AC: 3301 AN: 5142

South Asian (SAS) AF: 0.727 AC: 3501 AN: 4816

European-Finnish (FIN) AF: 0.555 AC: 5826 AN: 10492

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36422 AN: 67832

Other (OTH) AF: 0.570 AC: 1203 AN: 2110

Alfa AF: 0.557 Hom.: 18189

Bravo AF: 0.594

Asia WGS AF: 0.701 AC: 2439 AN: 3478

EpiCase AF: 0.533

EpiControl AF: 0.529

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial Mediterranean fever (4)
-	-	3	not provided (3)
-	-	1	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	-0.81
CADD	Benign	0.82
DANN	Benign	0.23
PhyloP100		-1.0
Mutation Taster		=99/1	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: rs224207; hg19: chr16-3297175; COSMIC: COSV54819266;