16-3247181-C-T

Variant names:

• chr16-3247181-C-T
• rs224208
• NM_000243.3:c.1422G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000243.3(MEFV):​c.1422G>A​(p.Glu474Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,613,184 control chromosomes in the GnomAD database, including 261,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25921 hom., cov: 32)
  • Exomes 𝑓: 0.56 (235201 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.956
• Publications: 34 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):

• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever

  Inheritance: AR, SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 16-3247181-C-T is Benign according to our data. Variant chr16-3247181-C-T is described in ClinVar as Benign. ClinVar VariationId is 36500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.956 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.705 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.1422G>A	p.Glu474Glu	synonymous	Exon 5 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.789G>A	p.Glu263Glu	synonymous	Exon 4 of 9	NP_001185465.2	O15553-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1422G>A	p.Glu474Glu	synonymous	Exon 5 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.789G>A	p.Glu263Glu	synonymous	Exon 4 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*55G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88154 AN: 151450 Hom.: 25882 Cov.: 32

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.605 AC: 152060 AN: 251414 AF XY: 0.601

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.623

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.564 AC: 824214 AN: 1461616 Hom.: 235201 Cov.: 64 AF XY: 0.567 AC XY: 412023 AN XY: 727126

African (AFR) AF: 0.642 AC: 21486 AN: 33478

American (AMR) AF: 0.725 AC: 32420 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14383 AN: 26134

East Asian (EAS) AF: 0.615 AC: 24398 AN: 39698

South Asian (SAS) AF: 0.713 AC: 61508 AN: 86250

European-Finnish (FIN) AF: 0.562 AC: 30041 AN: 53408

Middle Eastern (MID) AF: 0.553 AC: 3190 AN: 5768

European-Non Finnish (NFE) AF: 0.542 AC: 602468 AN: 1111768

Other (OTH) AF: 0.568 AC: 34320 AN: 60390

GnomAD4 genome AF: 0.582 AC: 88251 AN: 151568 Hom.: 25921 Cov.: 32 AF XY: 0.587 AC XY: 43433 AN XY: 74046

African (AFR) AF: 0.637 AC: 26311 AN: 41318

American (AMR) AF: 0.622 AC: 9459 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1914 AN: 3464

East Asian (EAS) AF: 0.612 AC: 3151 AN: 5150

South Asian (SAS) AF: 0.726 AC: 3497 AN: 4820

European-Finnish (FIN) AF: 0.556 AC: 5819 AN: 10474

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36391 AN: 67812

Other (OTH) AF: 0.569 AC: 1202 AN: 2112

Alfa AF: 0.558 Hom.: 15285

Bravo AF: 0.590

Asia WGS AF: 0.681 AC: 2369 AN: 3478

EpiCase AF: 0.533

EpiControl AF: 0.529

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial Mediterranean fever (5)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.9
DANN	Benign	0.35
PhyloP100		-0.96
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: rs224208; hg19: chr16-3297181; COSMIC: COSV54819286;