16-3249468-C-A

Variant names:

• chr16-3249468-C-A
• rs11466024
• NM_000243.3:c.1223G>T
• MEFV p.Arg408Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6

The NM_000243.3(MEFV):c.1223G>T (p.Arg408Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000359 (AC=58) in the gnomAD database across 1,613,940 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000376. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R408Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2552); p.R408W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 457994)

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: -0.571
• Publications: 152 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: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000376 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00164) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 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.1223G>T p.Arg408Leu	missense	Exon 3 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.590G>T p.Arg197Leu	missense	Exon 2 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.1223G>Tp.Arg408Leu

Exon rankExon 3 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.590G>Tp.Arg197Leu

Exon rankExon 2 of 9

missense

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.1223G>T p.Arg408Leu	missense	Exon 3 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.590G>T p.Arg197Leu	missense	Exon 2 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.278-2222G>T	intron	Intron 1 of 6	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.1223G>Tp.Arg408Leu

Exon rankExon 3 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.590G>Tp.Arg197Leu

Exon rankExon 2 of 9

missense

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.278-2222G>T

Exon rankIntron 1 of 6

intron

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: 0.0000394	AC:6	Hom:0	AN:152210	Cov:33
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:250794	Cov:
GnomAD4 exome	AF: 0.0000356	AC:52	Hom:0	AN:1461730	Cov:32
GnomAD4 genome	AF: 0.0000394	AC:6	Hom:0	AN:152210	Cov:33
TOPMed (Bravo)	AF: 0.0000227	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:66	AN:463392	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9618	0.00 *	0	10426
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.000139	4	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000598	4	66888
SCHEMA(Schizophrenia)	0.0000779	9	115506	0.0000363	7	193098

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Familial Mediterranean fever (4)
-	-	1	Acute febrile neutrophilic dermatosis (1)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	1	-	Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.5
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.089	N
FuncVEP CTI	Pathogenic	0.92
GPN-Star LLR	N/A	-4.9
GPN-Star score	N/A	4.9
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.83	T
Mutation Taster	N/A	96/4	polymorphism
MutationAssessor	Uncertain	2.3	M
PhyloP100	Benign	-0.57
popEVE	Benign	-3.3
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Benign	0.043	D
Sift4G	Uncertain	0.045	D
Varity_R	N/A	0.078
VESM-3B	Benign	-7.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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: rs11466024;

hg19: chr16-3299468;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar