rs104895090

Positions:

• chr16-3243445-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000243.3(MEFV):​c.2042C>T​(p.Thr681Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.512

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 4 ACMG points.

• PM1: In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2042C>T	p.Thr681Ile	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*246C>T		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.2042C>T	p.Thr681Ile	missense_variant	10/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D;N
REVEL	Uncertain	0.40
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.27	B;.;.
Vest4		0.16
MutPred		0.76		Loss of disorder (P = 0.0367);.;.;
MVP		0.80
MPC		0.15
ClinPred		0.22	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.17

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: rs104895090; hg19: chr16-3293445;