16-3242502-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000243.3(MEFV):c.*639G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00808 in 162,604 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (16 hom., cov: 29)
  • Exomes 𝑓: 0.013 (3 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.299

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00772 (1171/151666) while in subpopulation SAS AF= 0.0539 (259/4806). AF 95% confidence interval is 0.0485. There are 16 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.*639G>A		3_prime_UTR_variant	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*1189G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.*639G>A		3_prime_UTR_variant	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1174 AN: 151550 Hom.: 17 Cov.: 29

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00665

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.0131 AC: 143 AN: 10938 Hom.: 3 Cov.: 0 AF XY: 0.0166 AC XY: 105 AN XY: 6312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00334

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.00463

Gnomad4 NFE exome AF: 0.00554

Gnomad4 OTH exome AF: 0.00794

GnomAD4 genome AF: 0.00772 AC: 1171 AN: 151666 Hom.: 16 Cov.: 29 AF XY: 0.00898 AC XY: 665 AN XY: 74070

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00664

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.000778

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00776

Gnomad4 OTH AF: 0.00998

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00638

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial Mediterranean fever Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.9
Dann	Benign	0.44

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: rs181380218; hg19: chr16-3292502;