NM_000243.3:c.2080A>C

Variant names:

• chr16-3243407-T-G
• rs61752717
• NM_000243.3:c.2080A>C
• MEFV p.Met694Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2PM5

The NM_000243.3(MEFV):c.2080A>C (p.Met694Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,882 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000299. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.M694V: Pathogenic (ClinVar VariationId 449657, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M694K: Uncertain_significance (ClinVar VariationId 803180, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 97487, 1 star); p.M694dup: Uncertain_significance (ClinVar VariationId 1785563, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Familial mediterranean fever (fmf).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527
• Publications: 9 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: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 3 benign (OR vs. background: 3.6).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000299 — very rare for AD+AR gene (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.M694V: Pathogenic (ClinVar VariationId 449657, 1 star); Other variants at the same amino acid residue (not pathogenic): p.M694K: Uncertain_significance (ClinVar VariationId 803180, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 97487, 1 star); p.M694dup: Uncertain_significance (ClinVar VariationId 1785563, 1 star)

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.2080A>C p.Met694Leu	missense	Exon 10 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.*284A>C	3_prime_UTR	Exon 9 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.2080A>Cp.Met694Leu

Exon rankExon 10 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.*284A>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.2080A>C p.Met694Leu	missense	Exon 10 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.*284A>C	3_prime_UTR	Exon 9 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.*713A>C	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.2080A>Cp.Met694Leu

Exon rankExon 10 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.*284A>C

Exon rankExon 9 of 9

3_prime_UTR

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.*713A>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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461882	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial Mediterranean fever (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	6.7
DANN	Benign	0.28
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.71	D
FuncVEP CTI	Benign	0.42
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
LIST_S2	Benign	0.060	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.99	T
Mutation Taster	N/A	5/95	disease causing
MutationAssessor	Benign	0.080	N
PhyloP100	Benign	0.53
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Benign	0.58	T
Varity_R	N/A	0.33
VESM-3B	Benign	-3.9

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: rs61752717;

hg19: chr16-3293407;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar