rs2234939

chr16-3243369-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000243.3(MEFV):c.2118G>A(p.Pro706=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,066 control chromosomes in the GnomAD database, including 34 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 0.0081 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (27 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -7.21

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-3243369-C-T is Benign according to our data. Variant chr16-3243369-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=7, Uncertain_significance=1}. Variant chr16-3243369-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00812 (1236/152196) while in subpopulation AFR AF= 0.0224 (928/41518). AF 95% confidence interval is 0.0212. There are 7 homozygotes in gnomad4. There are 576 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.2118G>A	p.Pro706=	synonymous_variant	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*322G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.2118G>A	p.Pro706=	synonymous_variant	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 1232 AN: 152078 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00364 AC: 916 AN: 251470 Hom.: 3 AF XY: 0.00316 AC XY: 429 AN XY: 135908

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00239 AC: 3498 AN: 1461870 Hom.: 27 Cov.: 32 AF XY: 0.00234 AC XY: 1702 AN XY: 727230

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00662

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00812 AC: 1236 AN: 152196 Hom.: 7 Cov.: 32 AF XY: 0.00774 AC XY: 576 AN XY: 74398

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00506 Hom.: 3

Bravo AF: 0.00941

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Benign:4

Likely 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.	Dec 09, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 24, 2023	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

not provided Benign:2

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 06, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2015

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. -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 16, 2020

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.69
Dann	Benign	0.63

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: rs2234939; hg19: chr16-3293369; COSMIC: COSV54825485; COSMIC: COSV54825485;