chr16-3242398-A-G

Variant names:

• chr16-3242398-A-G
• rs170387
• NM_000243.3:c.*743T>C

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.*743T>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 0.631 in 144,492 control chromosomes in the GnomAD database, including 28,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (28292 hom., cov: 23)
  • Exomes 𝑓: 0.50 (194 hom.)
• Consequence: MEFV NM_000243.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.11
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BP6: Variant 16-3242398-A-G is Benign according to our data. Variant chr16-3242398-A-G is described in ClinVar as [Benign]. Clinvar id is 319092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.*743T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*1293T>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.*743T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 90498 AN: 143184 Hom.: 28262 Cov.: 23

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.606

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.501 AC: 611 AN: 1220 Hom.: 194 Cov.: 0 AF XY: 0.500 AC XY: 409 AN XY: 818

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.550 AC: 22 AN: 40

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 5 AN: 10

East Asian (EAS) AF: 0.250 AC: 5 AN: 20

South Asian (SAS) AF: 0.657 AC: 323 AN: 492

European-Finnish (FIN) AF: 0.417 AC: 20 AN: 48

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.381 AC: 223 AN: 586

Other (OTH) AF: 0.550 AC: 11 AN: 20

GnomAD4 genome AF: 0.632 AC: 90572 AN: 143272 Hom.: 28292 Cov.: 23 AF XY: 0.636 AC XY: 44269 AN XY: 69648

African (AFR) AF: 0.718 AC: 27967 AN: 38954

American (AMR) AF: 0.667 AC: 9616 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2017 AN: 3372

East Asian (EAS) AF: 0.731 AC: 3485 AN: 4766

South Asian (SAS) AF: 0.765 AC: 3515 AN: 4596

European-Finnish (FIN) AF: 0.582 AC: 5243 AN: 9010

Middle Eastern (MID) AF: 0.591 AC: 150 AN: 254

European-Non Finnish (NFE) AF: 0.567 AC: 36932 AN: 65098

Other (OTH) AF: 0.625 AC: 1228 AN: 1964

Alfa AF: 0.415 Hom.: 960

Bravo AF: 0.627

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 12, 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	-1.1
CADD	Benign	0.35
DANN	Benign	0.18
PhyloP100		-3.1
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: rs170387; hg19: chr16-3292398;