16-3247181-C-T

Position:

• chr16-3247181-C-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.1422G>A​(p.Glu474Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,613,184 control chromosomes in the GnomAD database, including 261,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25921 hom., cov: 32)
  • Exomes 𝑓: 0.56 (235201 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.956

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]

MEFV (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 16-3247181-C-T is Benign according to our data. Variant chr16-3247181-C-T is described in ClinVar as [Benign]. Clinvar id is 36500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3247181-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.956 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1422G>A	p.Glu474Glu	synonymous_variant	5/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.789G>A	p.Glu263Glu	synonymous_variant	4/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1422G>A	p.Glu474Glu	synonymous_variant	5/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88154 AN: 151450 Hom.: 25882 Cov.: 32

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.605 AC: 152060 AN: 251414 Hom.: 47046 AF XY: 0.601 AC XY: 81603 AN XY: 135890

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.623

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.564 AC: 824214 AN: 1461616 Hom.: 235201 Cov.: 64 AF XY: 0.567 AC XY: 412023 AN XY: 727126

Gnomad4 AFR exome AF: 0.642

Gnomad4 AMR exome AF: 0.725

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.615

Gnomad4 SAS exome AF: 0.713

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.568

GnomAD4 genome AF: 0.582 AC: 88251 AN: 151568 Hom.: 25921 Cov.: 32 AF XY: 0.587 AC XY: 43433 AN XY: 74046

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.612

Gnomad4 SAS AF: 0.726

Gnomad4 FIN AF: 0.556

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.569

Alfa AF: 0.556 Hom.: 14490

Bravo AF: 0.590

Asia WGS AF: 0.681 AC: 2369 AN: 3478

EpiCase AF: 0.533

EpiControl AF: 0.529

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	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, 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	Genome-Nilou Lab	Jul 01, 2021	- -
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	- -

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

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	-0.58
CADD	Benign	4.9
DANN	Benign	0.35

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: rs224208; hg19: chr16-3297181; COSMIC: COSV54819286;