rs224207

Positions:

• chr16-3247175-T-C

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.1428A>G​(p.Gln476=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,124 control chromosomes in the GnomAD database, including 262,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26194 hom., cov: 32)
  • Exomes 𝑓: 0.56 (236098 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.03

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=-0.81).
• BP6: Variant 16-3247175-T-C is Benign according to our data. Variant chr16-3247175-T-C is described in ClinVar as [Benign]. Clinvar id is 255615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3247175-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 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.1428A>G	p.Gln476=	synonymous_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.795A>G	p.Gln265=	synonymous_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1428A>G	p.Gln476=	synonymous_variant	5/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88598 AN: 151460 Hom.: 26154 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.569

GnomAD3 exomes AF: 0.608 AC: 152877 AN: 251442 Hom.: 47564 AF XY: 0.603 AC XY: 81961 AN XY: 135900

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.658

Gnomad SAS exome AF: 0.728

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.565 AC: 825635 AN: 1461544 Hom.: 236098 Cov.: 63 AF XY: 0.568 AC XY: 412707 AN XY: 727090

Gnomad4 AFR exome AF: 0.647

Gnomad4 AMR exome AF: 0.725

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.639

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.571

GnomAD4 genome AF: 0.585 AC: 88697 AN: 151580 Hom.: 26194 Cov.: 32 AF XY: 0.589 AC XY: 43660 AN XY: 74064

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.642

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.555

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.570

Alfa AF: 0.555 Hom.: 14028

Bravo AF: 0.594

Asia WGS AF: 0.701 AC: 2439 AN: 3478

EpiCase AF: 0.533

EpiControl AF: 0.529

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, 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	-	- -

Familial Mediterranean fever Benign:4

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	- -
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. -

not provided Benign:3

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.82
DANN	Benign	0.23

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: rs224207; hg19: chr16-3297175; COSMIC: COSV54819266;