16-3254463-C-T

Position:

chr16-3254463-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000243.3(MEFV):c.605G>A(p.Arg202Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,602,838 control chromosomes in the GnomAD database, including 49,745 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 Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4074 hom., cov: 33)

Exomes 𝑓: 0.24 ( 45671 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -2.58

Variant links:

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]

MEFV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00396502).

BP6

Variant 16-3254463-C-T is Benign according to our data. Variant chr16-3254463-C-T is described in ClinVar as [Benign]. Clinvar id is 36512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3254463-C-T is described in Lovd as [Benign]. Variant chr16-3254463-C-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.605G>A	p.Arg202Gln	missense_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.277+1848G>A		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.605G>A	p.Arg202Gln	missense_variant	2/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31329

AN:

152092

Hom.:

4075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0691

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.301

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.0378

Gnomad SAS

AF:

0.0998

Gnomad FIN

AF:

0.343

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.238

AC:

54494

AN:

229238

Hom.:

7532

AF XY:

0.230

AC XY:

29031

AN XY:

126448

show subpopulations

Gnomad AFR exome

AF:

0.0651

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.0432

Gnomad SAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.243

AC:

352124

AN:

1450630

Hom.:

45671

Cov.:

AF XY:

0.239

AC XY:

172063

AN XY:

720704

show subpopulations

Gnomad4 AFR exome

AF:

0.0618

Gnomad4 AMR exome

AF:

0.349

Gnomad4 ASJ exome

AF:

0.223

Gnomad4 EAS exome

AF:

0.0370

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.337

Gnomad4 NFE exome

AF:

0.260

Gnomad4 OTH exome

AF:

0.221

GnomAD4 genome

AF:

0.206

AC:

31324

AN:

152208

Hom.:

4074

Cov.:

AF XY:

0.210

AC XY:

15601

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0689

Gnomad4 AMR

AF:

0.301

Gnomad4 ASJ

AF:

0.214

Gnomad4 EAS

AF:

0.0379

Gnomad4 SAS

AF:

0.0996

Gnomad4 FIN

AF:

0.343

Gnomad4 NFE

AF:

0.266

Gnomad4 OTH

AF:

0.208

Alfa

AF:

0.244

Hom.:

1192

Bravo

AF:

0.200

TwinsUK

AF:

0.249

AC:

925

ALSPAC

AF:

0.241

AC:

930

ESP6500AA

AF:

0.0651

AC:

280

ESP6500EA

AF:

0.240

AC:

1996

ExAC

AF:

0.223

AC:

26172

Asia WGS

AF:

0.0730

AC:

257

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 52% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial Mediterranean fever

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 41.265% in ExAC) based on the frequency threshold of 1.904% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2014

This alteration is classified as 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

Jan 20, 2022

- -

Familial Mediterranean fever, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0040

DANN

Benign

0.44

DEOGEN2

Benign

0.26

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.60

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

0.30

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

0.73

Polyphen

0.0020

Vest4

0.048

MPC

0.13

ClinPred

0.00059

GERP RS

-5.2

Varity_R

0.017

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over