16-3249765-G-C

Variant names:

• chr16-3249765-G-C
• rs104895155
• NM_000243.3:c.926C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000243.3(MEFV):​c.926C>G​(p.Thr309Arg) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T309M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• 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):

• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061330557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.926C>G	p.Thr309Arg	missense_variant	Exon 3 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.293C>G	p.Thr98Arg	missense_variant	Exon 2 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.926C>G	p.Thr309Arg	missense_variant	Exon 3 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Benign	0.73
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.;.;.
PhyloP100		0.27
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.93	N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.060	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0080	B;.;.;.
Vest4		0.19
MutPred		0.45		Loss of glycosylation at T309 (P = 0.0092);.;.;.;
MVP		0.47
MPC		0.13
ClinPred		0.044	T
GERP RS		0.31
Varity_R		0.062
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs104895155; hg19: chr16-3299765;