MEFV p.Arg408Gln

Variant names:

• chr16-3249468-C-T
• rs11466024
• NM_000243.3:c.1223G>A
• MEFV p.Arg408Gln

Your query was ambiguous. Multiple possible variants found:

• chr16-3249468-C-T
• chr16-3249467-CC-TT

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BS2

The NM_000243.3(MEFV):c.1223G>A (p.Arg408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0101 (AC=16,233) in the gnomAD database across 1,614,052 control chromosomes, including 193 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0498. In-silico predictor (REVEL) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R408L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 457995); p.R408W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 457994) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Familial mediterranean fever (fmf); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (165 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12 B:7 O:1
• Conservation: PhyloP100: -0.571
• Publications: 173 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 -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 193.; Very high cumulative gnomAD AC = 16233 (any gene).

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>A p.Arg408Gln	missense	Exon 3 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.590G>A p.Arg197Gln	missense	Exon 2 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.1223G>Ap.Arg408Gln

Exon rankExon 3 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.590G>Ap.Arg197Gln

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>A p.Arg408Gln	missense	Exon 3 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.590G>A p.Arg197Gln	missense	Exon 2 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.278-2222G>A	intron	Intron 1 of 6	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.1223G>Ap.Arg408Gln

Exon rankExon 3 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.590G>Ap.Arg197Gln

Exon rankExon 2 of 9

missense

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.278-2222G>A

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: 0.0115	AC:1752	Hom:29	AN:152208	Cov:33
GnomAD2 exomes	AF: 0.0132	AC:3314	Hom:	AN:250794	Cov:
GnomAD4 exome	AF: 0.00991	AC:14481	Hom:165	AN:1461726	Cov:32
GnomAD4 genome	AF: 0.0115	AC:1752	Hom:28	AN:152326	Cov:33
TOPMed (Bravo)	AF: 0.0105	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0111	AC:5122	Hom:66	AN:463392	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0111	AC:26	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0470	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00569	AC:74	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.0430	AC:151	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0360	AC:257	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0143	AC:27	Hom:	AN:1882	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0476	AC:5827	Hom:140	AN:122502	Cov:
Turkish Variome	AF: 0.0136	AC:90	Hom:0	AN:6638	Cov:
UK10K	AF: 0.00820	AC:62	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0590	AC:529	Hom:21	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00882 *	98	11106	0.00925 *	163	17616
BipEx(Bipolar disorder (including schizoaffective))	0.00788	224	28420	0.00728	210	28844
Epi25(Epilepsy)	0.0132	555	41958	0.0100	670	66888
SCHEMA(Schizophrenia)	0.0239	2964	123936	0.0192	3708	193124

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
1	4	4	not provided (9)
-	5	1	Familial Mediterranean fever (7)
-	1	2	not specified (3)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	10
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
FuncVEP CTI	Benign	0.073
GPN-Star LLR	N/A	-1.3
GPN-Star score	N/A	1.3
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	98/2	disease causing (ClinVar)
MutationAssessor	Benign	0.73	N
PhyloP100	Benign	-0.57
popEVE	Benign	-2.9
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.035
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Varity_R	N/A	0.038
VESM-3B	Benign	-5.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DG_spliceai	Uncertain	0.23	Position offset: -1
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Uncertain	0.23	Details are displayed if max score is > 0.2

Showing 3 of 3 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;

COSMIC: COSV54819785;

COSMIC: COSV54819785;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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