16-3254573-G-T

Position:

• chr16-3254573-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):​c.495C>A​(p.Ala165=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,577,888 control chromosomes in the GnomAD database, including 169,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17488 hom., cov: 33)
  • Exomes 𝑓: 0.45 (152465 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 0.566

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-3254573-G-T is Benign according to our data. Variant chr16-3254573-G-T is described in ClinVar as [Benign]. Clinvar id is 36511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3254573-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.566 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.495C>A	p.Ala165=	synonymous_variant	2/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.277+1738C>A		intron_variant			NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.495C>A	p.Ala165=	synonymous_variant	2/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71512 AN: 151942 Hom.: 17459 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.430 AC: 82493 AN: 191956 Hom.: 19611 AF XY: 0.410 AC XY: 43586 AN XY: 106430

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.453 AC: 646049 AN: 1425828 Hom.: 152465 Cov.: 69 AF XY: 0.444 AC XY: 314359 AN XY: 707504

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.471 AC: 71597 AN: 152060 Hom.: 17488 Cov.: 33 AF XY: 0.467 AC XY: 34729 AN XY: 74336

Gnomad4 AFR AF: 0.503

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.514

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.464

Alfa AF: 0.481 Hom.: 6640

Bravo AF: 0.480

Asia WGS AF: 0.233 AC: 814 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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: 67.678% 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. A synonymous variant not located in a splice region. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 60% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial Mediterranean fever Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2016

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

Dec 12, 2016

- -

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.64

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: rs224223; hg19: chr16-3304573; COSMIC: COSV54818155;