16-3242112-C-G

Variant names:

• chr16-3242112-C-G
• rs142648477
• NM_000243.3:c.*1029G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000243.3(MEFV):​c.*1029G>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 0.00341 in 166,960 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (2 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.303
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*1029G>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1579G>C		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.*1029G>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 518 AN: 152114 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00346 AC: 51 AN: 14728 Hom.: 2 Cov.: 0 AF XY: 0.00298 AC XY: 28 AN XY: 9390

African (AFR) AF: 0.00 AC: 0 AN: 86

American (AMR) AF: 0.00329 AC: 1 AN: 304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 262

East Asian (EAS) AF: 0.00 AC: 0 AN: 52

South Asian (SAS) AF: 0.00237 AC: 14 AN: 5898

European-Finnish (FIN) AF: 0.00312 AC: 3 AN: 962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.00471 AC: 31 AN: 6588

Other (OTH) AF: 0.00377 AC: 2 AN: 530

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152232 Hom.: 2 Cov.: 31 AF XY: 0.00302 AC XY: 225 AN XY: 74450

African (AFR) AF: 0.000867 AC: 36 AN: 41542

American (AMR) AF: 0.00229 AC: 35 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00576 AC: 392 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00508 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.82
CADD	Benign	2.4
DANN	Benign	0.82
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: rs142648477; hg19: chr16-3292112;