16-3249468-CG-AA

Variant names:

• chr16-3249468-CG-AA
• NM_000243.3:c.1222_1223delCGinsTT
• MEFV p.Arg408Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000243.3(MEFV):c.1222_1223delCGinsTT (p.Arg408Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.R408Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2552); p.R408W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 457994)

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 0 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.

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.1222_1223delCGinsTT p.Arg408Leu	missense	N/A	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.589_590delCGinsTT p.Arg197Leu	missense	N/A	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.1222_1223delCGinsTTp.Arg408Leu

Exon rankN/A

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.589_590delCGinsTTp.Arg197Leu

Exon rankN/A

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.1222_1223delCGinsTT p.Arg408Leu	missense	N/A	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.589_590delCGinsTT p.Arg197Leu	missense	N/A	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.278-2223_278-2222delCGinsTT	intron	Intron 1 of 6	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.1222_1223delCGinsTTp.Arg408Leu

Exon rankN/A

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.589_590delCGinsTTp.Arg197Leu

Exon rankN/A

missense

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.278-2223_278-2222delCGinsTT

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	-0.14

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr16-3299468;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar