16-3242398-A-G

Position:

• chr16-3242398-A-G

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.*743T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 144,492 control chromosomes in the GnomAD database, including 28,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (28292 hom., cov: 23)
  • Exomes 𝑓: 0.50 (194 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.11

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=-1.05).
• BP6: Variant 16-3242398-A-G is Benign according to our data. Variant chr16-3242398-A-G is described in ClinVar as [Benign]. Clinvar id is 319092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*743T>C		3_prime_UTR_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1293T>C		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596	c.*743T>C		3_prime_UTR_variant	10/10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 90498 AN: 143184 Hom.: 28262 Cov.: 23

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.606

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.501 AC: 611 AN: 1220 Hom.: 194 Cov.: 0 AF XY: 0.500 AC XY: 409 AN XY: 818

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.550

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.632 AC: 90572 AN: 143272 Hom.: 28292 Cov.: 23 AF XY: 0.636 AC XY: 44269 AN XY: 69648

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.598

Gnomad4 EAS AF: 0.731

Gnomad4 SAS AF: 0.765

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.625

Alfa AF: 0.415 Hom.: 960

Bravo AF: 0.627

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial Mediterranean fever Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.35
DANN	Benign	0.18

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: rs170387; hg19: chr16-3292398;