rs224206

Positions:

• chr16-3247073-A-G
• chr16-3247073-A-T

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.1530T>C​(p.Asp510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,613,894 control chromosomes in the GnomAD database, including 266,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27683 hom., cov: 32)
  • Exomes 𝑓: 0.57 (238377 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -4.78

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=-0.97).
• BP6: Variant 16-3247073-A-G is Benign according to our data. Variant chr16-3247073-A-G is described in ClinVar as [Benign]. Clinvar id is 36503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3247073-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1530T>C	p.Asp510=	synonymous_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.897T>C	p.Asp299=	synonymous_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1530T>C	p.Asp510=	synonymous_variant	5/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90981 AN: 151926 Hom.: 27643 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.580

GnomAD3 exomes AF: 0.612 AC: 153868 AN: 251414 Hom.: 48215 AF XY: 0.606 AC XY: 82381 AN XY: 135906

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.656

Gnomad SAS exome AF: 0.728

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.568 AC: 829639 AN: 1461850 Hom.: 238377 Cov.: 73 AF XY: 0.570 AC XY: 414494 AN XY: 727228

Gnomad4 AFR exome AF: 0.692

Gnomad4 AMR exome AF: 0.729

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.544

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.599 AC: 91082 AN: 152044 Hom.: 27683 Cov.: 32 AF XY: 0.603 AC XY: 44835 AN XY: 74328

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.628

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.644

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.581

Alfa AF: 0.547 Hom.: 27485

Bravo AF: 0.608

Asia WGS AF: 0.703 AC: 2445 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Benign:5

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

not specified Benign:4

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 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	-0.97
CADD	Benign	0.074
DANN	Benign	0.31

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: rs224206; hg19: chr16-3297073; COSMIC: COSV54819248;