16-3243447-C-G

Variant names:

• chr16-3243447-C-G
• rs28940580
• NM_000243.3:c.2040G>C
• 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 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM5PP5_Strong

The NM_000243.3(MEFV):c.2040G>C (p.Met680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000576 (AC=93) in the gnomAD database across 1,614,134 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0012. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). 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: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:45 O:1
• Conservation: PhyloP100: -0.167
• Publications: 20 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 14 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).
	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 submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (45/45 total P/LP).

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>C p.Met680Ile	missense	Exon 10 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.*244G>C	3_prime_UTR	Exon 9 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.2040G>Cp.Met680Ile

Exon rankExon 10 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.*244G>C

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>C p.Met680Ile	missense	Exon 10 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.*244G>C	3_prime_UTR	Exon 9 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.*673G>C	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.2040G>Cp.Met680Ile

Exon rankExon 10 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.*244G>C

Exon rankExon 9 of 9

3_prime_UTR

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.*673G>C

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000460	AC:7	Hom:0	AN:152148	Cov:32
GnomAD2 exomes	AF: 0.000103	AC:26	Hom:	AN:251474	Cov:
GnomAD4 exome	AF: 0.0000581	AC:85	Hom:0	AN:1461868	Cov:32
GnomAD4 genome	AF: 0.0000525	AC:8	Hom:0	AN:152266	Cov:32
TOPMed (Bravo)	AF: 0.0000567	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000807	AC:6	Hom:0	AN:74306	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000770	AC:1	Hom:	AN:12994	Cov:
Turkish Variome	AF: 0.00669	AC:45	Hom:0	AN:6724	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000953	4	41958	0.000105	7	66888
SCHEMA(Schizophrenia)	0.00	0	76954	0.0000652	9	138070

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Familial Mediterranean fever (19)
16	-	-	not provided (16)
4	-	-	Familial Mediterranean fever, autosomal dominant (4)
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	-	-	Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	MEFV-related disorder (1)
1	-	-	See cases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.56
DANN	Benign	0.57
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.020	N
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	0.047	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 26 of 26 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