NM_000243.3:c.*639G>A

Variant names:

• chr16-3242502-C-T
• rs181380218
• NM_000243.3:c.*639G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*639G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1189G>A		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.*639G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

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

African (AFR) AF: 0.00 AC: 0 AN: 64

American (AMR) AF: 0.00334 AC: 6 AN: 1794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 94

East Asian (EAS) AF: 0.00 AC: 0 AN: 258

South Asian (SAS) AF: 0.0404 AC: 102 AN: 2524

European-Finnish (FIN) AF: 0.00463 AC: 1 AN: 216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00554 AC: 31 AN: 5600

Other (OTH) AF: 0.00794 AC: 3 AN: 378

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

African (AFR) AF: 0.00140 AC: 58 AN: 41328

American (AMR) AF: 0.00664 AC: 101 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5144

South Asian (SAS) AF: 0.0539 AC: 259 AN: 4806

European-Finnish (FIN) AF: 0.0112 AC: 117 AN: 10444

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00776 AC: 527 AN: 67950

Other (OTH) AF: 0.00998 AC: 21 AN: 2104

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

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: rs181380218; hg19: chr16-3292502;