NM_000243.3:c.*1056G>T

Variant names:

• chr16-3242085-C-A
• rs450021
• NM_000243.3:c.*1056G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000243.3(MEFV):​c.*1056G>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 0.596 in 155,548 control chromosomes in the GnomAD database, including 27,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27251 hom., cov: 32)
  • Exomes 𝑓: 0.62 (724 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.54
• Publications: 7 publications found

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]

MEFV Gene-Disease associations (from GenCC):

• familial Mediterranean fever

  Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 16-3242085-C-A is Benign according to our data. Variant chr16-3242085-C-A is described in ClinVar as [Benign]. Clinvar id is 319086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*1056G>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1606G>T		3_prime_UTR_variant	Exon 9 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.*1056G>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90418 AN: 151806 Hom.: 27210 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.615 AC: 2230 AN: 3624 Hom.: 724 Cov.: 0 AF XY: 0.634 AC XY: 1537 AN XY: 2424

African (AFR) AF: 0.813 AC: 13 AN: 16

American (AMR) AF: 0.661 AC: 41 AN: 62

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 20 AN: 40

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.696 AC: 1230 AN: 1768

European-Finnish (FIN) AF: 0.558 AC: 115 AN: 206

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.528 AC: 748 AN: 1418

Other (OTH) AF: 0.557 AC: 59 AN: 106

GnomAD4 genome AF: 0.596 AC: 90519 AN: 151924 Hom.: 27251 Cov.: 32 AF XY: 0.600 AC XY: 44508 AN XY: 74230

African (AFR) AF: 0.664 AC: 27494 AN: 41424

American (AMR) AF: 0.632 AC: 9650 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1960 AN: 3468

East Asian (EAS) AF: 0.614 AC: 3162 AN: 5152

South Asian (SAS) AF: 0.728 AC: 3510 AN: 4824

European-Finnish (FIN) AF: 0.560 AC: 5912 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37041 AN: 67942

Other (OTH) AF: 0.586 AC: 1232 AN: 2102

Alfa AF: 0.491 Hom.: 2784

Bravo AF: 0.604

Asia WGS AF: 0.693 AC: 2410 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial Mediterranean fever Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.98
CADD	Benign	0.69
DANN	Benign	0.25
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs450021; hg19: chr16-3292085;