rs224217

Variant names:

• chr16-3251757-G-A
• rs224217
• NM_000243.3:c.911-1977C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000243.3(MEFV):​c.911-1977C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 151,982 control chromosomes in the GnomAD database, including 15,059 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15059 hom., cov: 31)
• Consequence: MEFV NM_000243.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.911-1977C>T		intron_variant	Intron 2 of 9	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.278-1977C>T		intron_variant	Intron 1 of 8		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.911-1977C>T		intron_variant	Intron 2 of 9	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66306 AN: 151864 Hom.: 15045 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 66363 AN: 151982 Hom.: 15059 Cov.: 31 AF XY: 0.435 AC XY: 32270 AN XY: 74262

African (AFR) AF: 0.385 AC: 15977 AN: 41446

American (AMR) AF: 0.523 AC: 7978 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1409 AN: 3462

East Asian (EAS) AF: 0.152 AC: 788 AN: 5176

South Asian (SAS) AF: 0.227 AC: 1098 AN: 4828

European-Finnish (FIN) AF: 0.522 AC: 5501 AN: 10534

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32255 AN: 67958

Other (OTH) AF: 0.433 AC: 912 AN: 2104

Alfa AF: 0.449 Hom.: 5181

Bravo AF: 0.440

Asia WGS AF: 0.223 AC: 778 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.24
PhyloP100		0.081
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: rs224217; hg19: chr16-3301757;