16-3243407-T-C

Variant names:

• chr16-3243407-T-C
• rs61752717
• NM_000243.3:c.2080A>G
• MEFV p.Met694Val

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 20P and 2B. PS1 PS3 PM1 PM5 PP5_Very_Strong BP4 BS2_Supporting

The NM_000243.3(MEFV):​c.2080A>G​(p.Met694Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,614,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000629034: Experimental studies have shown that this missense change affects MEFV function (PMID:24318677)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M694I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:55 O:2
• Conservation: PhyloP100: 0.527
• Publications: 911 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, AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women's Health, Orphanet, ClinGen
• familial Mediterranean fever, autosomal dominant

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_000243.3 (MEFV) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000629034: Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677).; SCV000803512: Well-established functional studies show a deleterious effect (PMID:24318677).; SCV003841560: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797).; SCV004847545: in vitro functional studies show decreased capacity of the variant protein to suppress IL-8 secretion in synovial cell cultures and FMF-knock-in mice studies showed decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, thereby providing some evidence that this variant impacts protein function (Sugiyama 2014 PMID: 24318677, Park 2016 PMID: 27270401).; SCV005060943: Functional studies of this variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama et al. 2014).; SCV005397676: In vivo studies of this variant in human and murine cells indicate that this variant stimulates the release of pro-inflammatory signals (PMID: 24318677, 21600797).; SCV000279058: Multiple published functional and FMF-knock-in mice studies demonstrated the damaging effect of the M694V variant, e.g., showing loss of suppression of IL-8 secretion in vitro (Sugiyama et al., 2014) and decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo (Park, 2016);; SCV000604181: Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014).; SCV001550173: Further, functional studies of the M694V variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama_2014_PMID:24318677).; SCV004046213: Functional studies have shown that this missense change has a damaging effect on the function of the MEFV protein (PMID: 24318677, 27270401).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in NM_000243.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243405-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-3243407-T-C is Pathogenic according to our data. Variant chr16-3243407-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04752019). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,SD,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.2080A>G	p.Met694Val	missense	Exon 10 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.*284A>G		3_prime_UTR	Exon 9 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.2080A>G	p.Met694Val	missense	Exon 10 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.*284A>G		3_prime_UTR	Exon 9 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*713A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000176

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000282 AC: 71 AN: 251478 AF XY: 0.000294

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461882 Hom.: 3 Cov.: 32 AF XY: 0.000195 AC XY: 142 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1112012

Other (OTH) AF: 0.000927 AC: 56 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74442

African (AFR) AF: 0.0000722 AC: 3 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68002

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000249 Hom.: 1

Bravo AF: 0.000223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
16	-	-	Familial Mediterranean fever (18)
12	-	-	Familial Mediterranean fever, autosomal dominant (12)
3	-	-	MEFV-related disorder (3)
2	-	-	Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (2)
1	-	-	Acute febrile neutrophilic dermatosis (1)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Recurrent fever (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.026	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.53
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Varity_R		0.43
gMVP		0.27
Mutation Taster		=21/79	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61752717;

hg19: chr16-3293407;