16-3242296-G-A

Variant names:

• chr16-3242296-G-A
• rs371608683
• NM_000243.3:c.*845C>T

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.*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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.355
• Publications: 0 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=-0.94).
• 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 the male GnomAd4 subpopulation. Median coverage is 25. 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 14 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*845C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1395C>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.*845C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 100 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.0102 AC: 1 AN: 98

American (AMR) AF: 0.00276 AC: 1 AN: 362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 238

East Asian (EAS) AF: 0.00 AC: 0 AN: 44

South Asian (SAS) AF: 0.000903 AC: 6 AN: 6648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 36

European-Non Finnish (NFE) AF: 0.00127 AC: 9 AN: 7086

Other (OTH) AF: 0.00168 AC: 1 AN: 594

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

African (AFR) AF: 0.0403 AC: 921 AN: 22854

American (AMR) AF: 0.00427 AC: 37 AN: 8662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2292

East Asian (EAS) AF: 0.00 AC: 0 AN: 3070

South Asian (SAS) AF: 0.00 AC: 0 AN: 1992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6944

Middle Eastern (MID) AF: 0.00450 AC: 1 AN: 222

European-Non Finnish (NFE) AF: 0.00250 AC: 116 AN: 46336

Other (OTH) AF: 0.00696 AC: 9 AN: 1294

Alfa AF: 0.00613 Hom.: 0

Bravo AF: 0.00829

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial Mediterranean fever Uncertain:1

Jan 12, 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	-0.94
CADD	Benign	4.6
DANN	Benign	0.37
PhyloP100		0.35
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: rs371608683; hg19: chr16-3292296;