rs11466030

chr16-3246998-G-Achr16-3246998-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000243.3(MEFV):c.1587+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,612,596 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (13 hom.)
• Consequence: MEFV NM_000243.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.68

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=-0.93).
• BP6: Variant 16-3246998-G-A is Benign according to our data. Variant chr16-3246998-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3246998-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00825 (1256/152292) while in subpopulation AFR AF= 0.0271 (1128/41560). AF 95% confidence interval is 0.0258. There are 20 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.1587+18C>T		intron_variant		ENST00000219596.6
MEFV	NM_001198536.2	c.954+18C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.1587+18C>T		intron_variant		1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1253 AN: 152174 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00248 AC: 621 AN: 250266 Hom.: 10 AF XY: 0.00176 AC XY: 239 AN XY: 135422

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000807 AC: 1178 AN: 1460304 Hom.: 13 Cov.: 30 AF XY: 0.000709 AC XY: 515 AN XY: 726520

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00825 AC: 1256 AN: 152292 Hom.: 20 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74460

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00894

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	MEFV: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2016	Variant summary: The MEFV c.1587+18C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 375/120722 control chromosomes (5 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0311653 (322/10332). This frequency is slightly above the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Based on high frequency in controls and in silico splicing predictions, this variant was classified as likely benign. -

Familial Mediterranean fever Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -

Acute febrile neutrophilic dermatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Familial Mediterranean fever, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.072
Dann	Benign	0.36

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: rs11466030; hg19: chr16-3296998;