rs224225

Positions:

• chr16-3254762-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):​c.306T>C​(p.Asp102Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,612,084 control chromosomes in the GnomAD database, including 175,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17586 hom., cov: 33)
  • Exomes 𝑓: 0.46 (157837 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: -0.0840

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-3254762-A-G is Benign according to our data. Variant chr16-3254762-A-G is described in ClinVar as [Benign]. Clinvar id is 36509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3254762-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.084 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.306T>C	p.Asp102Asp	synonymous_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.277+1549T>C		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.306T>C	p.Asp102Asp	synonymous_variant	2/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71757 AN: 152018 Hom.: 17555 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.443 AC: 109255 AN: 246370 Hom.: 26555 AF XY: 0.426 AC XY: 57263 AN XY: 134418

Gnomad AFR exome AF: 0.507

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.163

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.516

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.456 AC: 665515 AN: 1459948 Hom.: 157837 Cov.: 57 AF XY: 0.448 AC XY: 325088 AN XY: 726320

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.506

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.433

GnomAD4 genome AF: 0.472 AC: 71845 AN: 152136 Hom.: 17586 Cov.: 33 AF XY: 0.469 AC XY: 34896 AN XY: 74380

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.514

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.464

Alfa AF: 0.474 Hom.: 25178

Bravo AF: 0.481

Asia WGS AF: 0.240 AC: 839 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 61.662% in ExAC) based on the frequency threshold of 1.904% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -

Familial Mediterranean fever Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.6
DANN	Benign	0.26

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: rs224225; hg19: chr16-3304762; COSMIC: COSV54819764;