chr16-3244246-G-A

Position:

• chr16-3244246-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000243.3(MEFV):​c.1759+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,613,954 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (245 hom.)
• Consequence: MEFV NM_000243.3 splice_region, intron
• Scores: Splicing: ADA: 0.000007063
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -1.76

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-3244246-G-A is Benign according to our data. Variant chr16-3244246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3244246-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1759+8C>T		splice_region_variant, intron_variant		ENST00000219596.6
MEFV	NM_001198536.2	c.1126+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1759+8C>T		splice_region_variant, intron_variant		1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 703 AN: 151990 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00816

GnomAD3 exomes AF: 0.00930 AC: 2337 AN: 251346 Hom.: 124 AF XY: 0.00935 AC XY: 1270 AN XY: 135834

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00368 AC: 5377 AN: 1461846 Hom.: 245 Cov.: 36 AF XY: 0.00391 AC XY: 2843 AN XY: 727218

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0877

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00462 AC: 702 AN: 152108 Hom.: 25 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74356

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00855

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00493

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Benign:5 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 13, 2018	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 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. -

Acute febrile neutrophilic dermatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs77380520; hg19: chr16-3294246;