chr16-3254739-A-G

Position:

• chr16-3254739-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000219596.6(MEFV):​c.329T>C​(p.Leu110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,772 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L110L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (15 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (121 hom.)
• Consequence: MEFV ENST00000219596.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 0.501

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020012558).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.329T>C	p.Leu110Pro	missense_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.277+1572T>C		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.329T>C	p.Leu110Pro	missense_variant	2/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152170 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0797

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00657 AC: 1625 AN: 247318 Hom.: 61 AF XY: 0.00605 AC XY: 816 AN XY: 134804

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.0842

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00236 AC: 3448 AN: 1460482 Hom.: 121 Cov.: 64 AF XY: 0.00228 AC XY: 1656 AN XY: 726570

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0753

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152290 Hom.: 15 Cov.: 34 AF XY: 0.00309 AC XY: 230 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0797

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00295 Hom.: 21

Bravo AF: 0.00313

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00620 AC: 750

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in both the heterozygous and homozygous states in unaffected individuals and in individuals with familial Mediterranean fever (Kim et al., 2006; Tomiyama et al., 2008); This variant is associated with the following publications: (PMID: 24965843, 17329916, 22989844, 23166428, 24797171, 24598070, 10854105, 24929125, 20041150, 25073670, 22534884, 26332735, 29017770, 28482392, 29178647, 26537665, 19967574, 18328141, 25261100, 29642170, 26457478, 29526930, 29151129, 24661635, 32199921, 32735870) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -

Familial Mediterranean fever Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2022	Variant summary: MEFV c.329T>C (p.Leu110Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0066 in 247780 control chromosomes, predominantly at a frequency of 0.084 within the East Asian subpopulation in the gnomAD database, including 61 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever phenotype (0.022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, the variant c.329T>C has also been commonly reported in FMF patients, primarily in the same allele (in cis) with p.E148Q, both in heterozygote and homozygote phases. In addition, multiple publications show lack of cosegregation for the variant and disease (Oshima_2010, Berdeli_2011, and Kim_2007). In Japanese population, the variant's allele frequency is higher in patients than in controls. Case-control studies in Japanese population indicate this variant may associate with increased risk of FMF (OR= 1.78, Migita_2016; OR=4.81, Tsuchiya-Suzuki_2009). Larger case-control studies are needed to validate these findings. At least one functional study demonstrated no damaging effect of this variant (Honda_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of uncertain significance for the variant (Van Gijn_2018). Based on the data available at this time, it is unknown whether this variant represents a low penetrance mild common pathogenic variant, modifier, or a risk allele. Therefore, this variant was classified as uncertain significance, until additional information becomes available. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.16
Sift	Benign	0.091	T
Sift4G	Benign	0.27	T
Polyphen		0.65	P
Vest4		0.086
MVP		0.51
MPC		0.19
ClinPred		0.0092	T
GERP RS		-1.5
Varity_R		0.047
gMVP		0.20

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: rs11466018; hg19: chr16-3304739;