chr16-3246429-G-A

Variant names:

• chr16-3246429-G-A
• rs224204
• NM_000243.3:c.1610+96C>T

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.1610+96C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,418,208 control chromosomes in the GnomAD database, including 168,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16399 hom., cov: 31)
  • Exomes 𝑓: 0.49 (152164 hom.)
• Consequence: MEFV NM_000243.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.212
• Publications: 22 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=-0.9).
• BP6: Variant 16-3246429-G-A is Benign according to our data. Variant chr16-3246429-G-A is described in ClinVar as Benign. ClinVar VariationId is 439879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1610+96C>T		intron	N/A	NP_000234.1
	MEFV	NM_001198536.2		c.977+96C>T		intron	N/A	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1610+96C>T		intron	N/A	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.977+96C>T		intron	N/A	ENSP00000438711.1
	MEFV	ENST00000539145.5	TSL:1	n.*243+96C>T		intron	N/A	ENSP00000444471.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70117 AN: 151760 Hom.: 16382 Cov.: 31

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.451

GnomAD4 exome AF: 0.487 AC: 617222 AN: 1266330 Hom.: 152164 Cov.: 17 AF XY: 0.484 AC XY: 309042 AN XY: 638836

African (AFR) AF: 0.377 AC: 11008 AN: 29202

American (AMR) AF: 0.643 AC: 27789 AN: 43202

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 10799 AN: 24718

East Asian (EAS) AF: 0.581 AC: 22135 AN: 38122

South Asian (SAS) AF: 0.423 AC: 34453 AN: 81370

European-Finnish (FIN) AF: 0.534 AC: 27556 AN: 51608

Middle Eastern (MID) AF: 0.427 AC: 2050 AN: 4806

European-Non Finnish (NFE) AF: 0.485 AC: 455743 AN: 939500

Other (OTH) AF: 0.477 AC: 25689 AN: 53802

GnomAD4 genome AF: 0.462 AC: 70171 AN: 151878 Hom.: 16399 Cov.: 31 AF XY: 0.467 AC XY: 34666 AN XY: 74232

African (AFR) AF: 0.383 AC: 15840 AN: 41398

American (AMR) AF: 0.538 AC: 8220 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3468

East Asian (EAS) AF: 0.582 AC: 3001 AN: 5158

South Asian (SAS) AF: 0.417 AC: 2005 AN: 4806

European-Finnish (FIN) AF: 0.534 AC: 5630 AN: 10548

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32533 AN: 67912

Other (OTH) AF: 0.449 AC: 948 AN: 2112

Alfa AF: 0.467 Hom.: 6694

Bravo AF: 0.466

Asia WGS AF: 0.487 AC: 1693 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Familial Mediterranean fever (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.34
PhyloP100		0.21
Mutation Taster		=11/89	disease causing

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: rs224204; hg19: chr16-3296429; COSMIC: COSV54824405;