rs61732424

chr16-3247136-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000243.3(MEFV):c.1467G>A(p.Gln489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,236 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10 O:1
• Conservation: PhyloP100: 0.775

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-3247136-C-T is Benign according to our data. Variant chr16-3247136-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97446.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, not_provided=1, Likely_benign=3, Uncertain_significance=1}. Variant chr16-3247136-C-T is described in Lovd as [Benign]. Variant chr16-3247136-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.775 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1467G>A	p.Gln489=	synonymous_variant	5/10	ENST00000219596.6
MEFV	NM_001198536.2	c.834G>A	p.Gln278=	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1467G>A	p.Gln489=	synonymous_variant	5/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 495 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00363 AC: 914 AN: 251496 Hom.: 5 AF XY: 0.00366 AC XY: 497 AN XY: 135922

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00459

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00372 AC: 5440 AN: 1461872 Hom.: 16 Cov.: 65 AF XY: 0.00356 AC XY: 2591 AN XY: 727240

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.00378 AC XY: 282 AN XY: 74506

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00349 Hom.: 1

Bravo AF: 0.00195

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Benign:2 Other:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 19, 2019	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MEFV: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2017	Variant summary: The MEFV c.1467G>A (p.Gln489Gln) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this substitution along with 5/5 splice prediction tools predicting the variant not to have a significance impact on normal splicing. The variant was found in 460/121412 control chromosomes (2 homozygotes) at a frequency of 0.0037888, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. In addition, a clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

This alteration is classified as likely 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. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.3
Dann	Benign	0.55

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: rs61732424; hg19: chr16-3297136;