rs28940580

Variant names:

• chr16-3243447-C-A
• rs28940580
• NM_000243.3:c.2040G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3243447-C-A
• chr16-3243447-C-G
• chr16-3243447-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PS1_Very_Strong PM2 PM5 PP5_Very_Strong BP4

The NM_000243.3(MEFV):​c.2040G>T​(p.Met680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M680L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.167
• Publications: 491 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, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS1: Transcript NM_000243.3 (MEFV) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243449-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97480.
• PP5: Variant 16-3243447-C-A is Pathogenic according to our data. Variant chr16-3243447-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 234365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32046145). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.2040G>T	p.Met680Ile	missense	Exon 10 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.*244G>T		3_prime_UTR	Exon 9 of 9	NP_001185465.2	O15553-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.2040G>T	p.Met680Ile	missense	Exon 10 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.*244G>T		3_prime_UTR	Exon 9 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*673G>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Familial Mediterranean fever (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.00021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.58
DANN	Benign	0.58
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.60	N
PhyloP100		-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
Polyphen		0.0	B
Vest4		0.30
MutPred		0.82		Gain of catalytic residue at M680 (P = 0.0329)
MVP		0.54
MPC		0.13
ClinPred		0.80	D
GERP RS		-3.3
Varity_R		0.23
gMVP		0.18
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28940580; hg19: chr16-3293447;