chr16-3242296-G-A

Position:

• chr16-3242296-G-A

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.*845C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00997 in 110,518 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 25)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.355

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=-0.94).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1084/94368) while in subpopulation AFR AF= 0.0403 (921/22854). AF 95% confidence interval is 0.0381. There are 14 homozygotes in gnomad4. There are 515 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.*845C>T		3_prime_UTR_variant	10/10	ENST00000219596.6
MEFV	NM_001198536.2	c.*1395C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.*845C>T		3_prime_UTR_variant	10/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1083 AN: 94326 Hom.: 15 Cov.: 25

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00427

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00427

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00701

GnomAD4 exome AF: 0.00111 AC: 18 AN: 16150 Hom.: 1 Cov.: 0 AF XY: 0.000855 AC XY: 9 AN XY: 10524

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000903

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.0115 AC: 1084 AN: 94368 Hom.: 14 Cov.: 25 AF XY: 0.0113 AC XY: 515 AN XY: 45634

Gnomad4 AFR AF: 0.0403

Gnomad4 AMR AF: 0.00427

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00696

Alfa AF: 0.00613 Hom.: 0

Bravo AF: 0.00829

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 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, 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	-0.94
CADD	Benign	4.6
DANN	Benign	0.37

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: rs371608683; hg19: chr16-3292296;