NM_000243.3:c.2040G>T

Variant names:

• chr16-3243447-C-A
• rs28940580
• NM_000243.3:c.2040G>T
• MEFV p.Met680Ile

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPS3PM2PM5PP5_Strong

The NM_000243.3(MEFV):c.2040G>T (p.Met680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004505253: Experimental studies have shown that this missense change affects MEFV function (PMID:21600797).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.M680L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 97480) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Familial mediterranean fever (fmf).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.167
• Publications: 553 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, STRONG, SUPPORTIVE Submitted by: Myriad Women's Health, Natera, ClinGen, Orphanet, PanelApp Australia
• familial Mediterranean fever, autosomal dominant

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 2 P/LP entries with the same amino acid change (highest review level: 2 stars).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004505253: Experimental studies have shown that this missense change affects MEFV function (PMID: 21600797).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00164) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.M680L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 97480)
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MEFV NM_000243.3	MANE Select	c.2040G>T p.Met680Ile	missense	Exon 10 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.*244G>T	3_prime_UTR	Exon 9 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.2040G>Tp.Met680Ile

Exon rankExon 10 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.*244G>T

Exon rankExon 9 of 9

3_prime_UTR

Prot: NP_001185465.2UniProt: D2DTW2O15553-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MEFV ENST00000219596.6	TSL:1MANE Select	c.2040G>T p.Met680Ile	missense	Exon 10 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.*244G>T	3_prime_UTR	Exon 9 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.*673G>T	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.2040G>Tp.Met680Ile

Exon rankExon 10 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.*244G>T

Exon rankExon 9 of 9

3_prime_UTR

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.*673G>T

Exon rankExon 7 of 7

3_prime_UTR

Prot: ENSP00000444471.1UniProt: F6TF35

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Familial Mediterranean fever (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.00021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.58
DANN	Benign	0.58
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.098	N
FuncVEP CTI	Pathogenic	0.80
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	-0.60	N
PhyloP100	Benign	-0.17
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.35
Sift	Benign	0.36	T
Sift4G	Benign	0.48	T
Varity_R	N/A	0.23
VESM-3B	Benign	-2.2

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28940580;

hg19: chr16-3293447;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar