16-3243008-C-T

Position:

• chr16-3243008-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000219596.6(MEFV):​c.*133G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,027,446 control chromosomes in the GnomAD database, including 1,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (311 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1619 hom.)
• Consequence: MEFV ENST00000219596.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.191

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-3243008-C-T is Benign according to our data. Variant chr16-3243008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 224066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243008-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*133G>A		3_prime_UTR_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*683G>A		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.*133G>A		3_prime_UTR_variant	10/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3033 AN: 152098 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0185 AC: 16172 AN: 875230 Hom.: 1619 Cov.: 12 AF XY: 0.0180 AC XY: 8107 AN XY: 449586

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.00355

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.0543

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0200 AC: 3038 AN: 152216 Hom.: 311 Cov.: 32 AF XY: 0.0241 AC XY: 1795 AN XY: 74412

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.327

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.0591

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00532 Hom.: 43

Bravo AF: 0.0198

Asia WGS AF: 0.167 AC: 578 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	case-control	Atomic Energy Commission of Syria (AECS)	Jan 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Acute febrile neutrophilic dermatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.64

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: rs2075849; hg19: chr16-3293008; COSMIC: COSV99560166; COSMIC: COSV99560166;