rs104895128

Positions:

• chr16-3243593-C-A
• chr16-3243593-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000243.3(MEFV):​c.1894G>T​(p.Gly632Cys) 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. 14/21 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. G632A) 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: 0.248

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243593-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97467.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Likely_pathogenic=2, not_provided=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22969016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1894G>T	p.Gly632Cys	missense_variant	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*98G>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1894G>T	p.Gly632Cys	missense_variant	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.081
Sift	Uncertain	0.011	D;D;D
Sift4G	Benign	0.064	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.22
MutPred		0.47		Loss of disorder (P = 0.0148);.;.;
MVP		0.54
MPC		0.50
ClinPred		0.38	T
GERP RS		-2.4
Varity_R		0.58
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs104895128; hg19: chr16-3293593; COSMIC: COSV54818469; COSMIC: COSV54818469;