rs11466047

chr16-3243324-G-Achr16-3243324-G-C

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.2163C>T(p.Phe721=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,172 control chromosomes in the GnomAD database, including 14 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 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (7 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.131

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=-0.84).
• BP6: Variant 16-3243324-G-A is Benign according to our data. Variant chr16-3243324-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458000.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr16-3243324-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.131 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (828/152286) while in subpopulation AFR AF= 0.0186 (771/41548). AF 95% confidence interval is 0.0175. There are 7 homozygotes in gnomad4. There are 381 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.2163C>T	p.Phe721=	synonymous_variant	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*367C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.2163C>T	p.Phe721=	synonymous_variant	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152168 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251488 Hom.: 2 AF XY: 0.00112 AC XY: 152 AN XY: 135920

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000664 AC: 970 AN: 1461886 Hom.: 7 Cov.: 32 AF XY: 0.000554 AC XY: 403 AN XY: 727240

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152286 Hom.: 7 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74460

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00641

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2016	Variant summary: The MEFV c.2163C>T (p.Phe721Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 215/121666 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0180665 (188/10406). The frequency in Africans is similar to estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Although there are no exact prevalence reports of FMF in African populations (unlike in other Mediterranean populations where this disease is common), we can consider the prevalence of FMF in Africans to be relatively lower. Therefore, the observed frequency of this variant which reaches ~2% (1.8% in NHLBI ESP and ExAC and 3.4% in HapMap) across multiple African populations is an indication that this variant is unlikely to have a pathogenic outcome or uncertain significance (maximum expected allele frequency for a pathogenic variant in MEFV is 2.2% when overall prevalence is taken at 1 in 400). Additionally, there are two homozygotes reported in the African cohort from ExAC. If only the observed frequencies in African populations were compared with ethnicity-specific disease prevalence (such as rare prevalence in Africans), the pbGP score would support for a benign outcome. Tchernitchko, 2003 reports one non-African patient with the variant, which authors state is in compound heterozygous form with a pathogenic variant (M694I/F721F); however, they do not specify whether a familial segregation study was performed to assign the phase of the variants. Taken together, this variant is classified as likely benign until additional information is available. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Acute febrile neutrophilic dermatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 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. -

Familial Mediterranean fever, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.86
Dann	Benign	0.40

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: rs11466047; hg19: chr16-3293324; COSMIC: COSV54821440; COSMIC: COSV54821440;