NM_000243.3:c.442G>T

Variant names:

• chr16-3254626-C-A
• rs3743930
• NM_000243.3:c.442G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000243.3(MEFV):​c.442G>T​(p.Glu148*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEFV NM_000243.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.734
• Publications: 676 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):

• familial Mediterranean fever

  Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever, autosomal dominant

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.442G>T	p.Glu148*	stop_gained	Exon 2 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.277+1685G>T		intron	N/A	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.442G>T	p.Glu148*	stop_gained	Exon 2 of 10	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.277+1685G>T		intron	N/A	ENSP00000438711.1
	MEFV	ENST00000570511.5	TSL:1	n.442G>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.73
Vest4		0.75
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743930; hg19: chr16-3304626;