rs61732425

Variant names:

• chr16-3254735-C-T
• rs61732425
• NM_000243.3:c.333G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000243.3(MEFV):​c.333G>A​(p.Gly111Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,612,880 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.201
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-3254735-C-T is Benign according to our data. Variant chr16-3254735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.201 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.333G>A	p.Gly111Gly	synonymous	Exon 2 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.277+1576G>A		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.333G>A	p.Gly111Gly	synonymous	Exon 2 of 10	ENSP00000219596.1
	MEFV	ENST00000570511.5	TSL:1	n.333G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1
	MEFV	ENST00000541159.5	TSL:1	c.277+1576G>A		intron	N/A	ENSP00000438711.1

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152252 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000796 AC: 197 AN: 247392 AF XY: 0.000586

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1460510 Hom.: 2 Cov.: 65 AF XY: 0.000261 AC XY: 190 AN XY: 726586

African (AFR) AF: 0.0108 AC: 361 AN: 33478

American (AMR) AF: 0.000984 AC: 44 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52092

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111984

Other (OTH) AF: 0.000646 AC: 39 AN: 60378

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152370 Hom.: 3 Cov.: 34 AF XY: 0.00293 AC XY: 218 AN XY: 74508

African (AFR) AF: 0.0105 AC: 438 AN: 41596

American (AMR) AF: 0.00190 AC: 29 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial Mediterranean fever (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Acute febrile neutrophilic dermatosis (1)
-	-	1	Autoinflammatory syndrome (1)
-	-	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	-0.78
CADD	Benign	2.0
DANN	Benign	0.51
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

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: rs61732425; hg19: chr16-3304735; COSMIC: COSV54822084;