16-3254532-C-T

Position:

• chr16-3254532-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2 PM5 BP4_Strong BP6

The NM_000243.3(MEFV):​c.536G>A​(p.Ser179Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,555,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S179I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: -0.462

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3254532-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073755383).
• BP6: Variant 16-3254532-C-T is Benign according to our data. Variant chr16-3254532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 664952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.536G>A	p.Ser179Asn	missense_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.277+1779G>A		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.536G>A	p.Ser179Asn	missense_variant	2/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000281 AC: 44 AN: 156324 Hom.: 0 AF XY: 0.000394 AC XY: 34 AN XY: 86284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 147 AN: 1403068 Hom.: 1 Cov.: 36 AF XY: 0.000157 AC XY: 109 AN XY: 694008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000460

Gnomad4 OTH exome AF: 0.0000688

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000219 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 19, 2023	The MEFV c.536G>A (p.Ser179Asn) missense variant results in the substitution of serine at amino acid position 179 with asparagine. This variant has been reported in an individual with familial Mediterranean fever (FMF) who also carried another missense variant (phase unknown) (PMID: 20721559). The c.536G>A variant was also identified in a homozygous state in two individuals with rheumatic heart disease. This variant resides between the PYD and BBox domain and 3-D protein modelling show that the c.536G>A variant impacts the protein structure and conformation as compared to normal protein (DOI: 10.4172/2155-9899.1000382). A different missense change at the same amino acid residue has also been reported in a compound heterozygous state with a pathogenic variant in a father and son with FMF (PMID: 14636645). This variant is reported in the Genome Aggregation Database in nine alleles at a frequency of 0.00186 in the South Asian population (version 3.1.2). Based on the available evidence, the c.536G>A (p.Ser179Asn) variant is classified as a variant of uncertain significance for familial Mediterranean fever. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense variant c.536G>Ap.Ser179Asn in the MEFV gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.03% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance/Likely benign. However, no details are available for independent assessment. The amino acid Ser at position 179 is changed to a Asn changing protein sequence and it might alter its composition and physico- chemical properties. Multiple lines of computational evidence Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism predict no damaging effect on protein structure and function for this variant. . The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 179 of the MEFV protein (p.Ser179Asn). This variant is present in population databases (rs104895125, gnomAD 0.2%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 20721559, 29579081). ClinVar contains an entry for this variant (Variation ID: 664952). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 16, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 14, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial Mediterranean fever, autosomal dominant Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense variant c.536G>Ap.Ser179Asn in MEFV gene has been reported previously in heterozygous state in individuals with familial Mediterranean fever Aita A, et al., 2018, Fujikura K, et al., 2015, Cornelius N, Duno M, 2011. The p.Ser179Asn variant is reported with 0.03% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Benign/ Uncertain Significance multiple submissions. However, study on multiple affected individuals and functional impact of the variant is not available. The amino acid Ser at position 179 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Acute febrile neutrophilic dermatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.48
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.046
Sift	Benign	0.30	T
Sift4G	Benign	0.40	T
Polyphen		0.0060	B
Vest4		0.099
MutPred		0.24		Loss of phosphorylation at S179 (P = 0.0023);
MVP		0.56
MPC		0.11
ClinPred		0.017	T
GERP RS		-1.5
Varity_R		0.059
gMVP		0.17

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: rs104895125; hg19: chr16-3304532;