chr16-3254762-A-G

Variant names:

• chr16-3254762-A-G
• rs224225
• NM_000243.3:c.306T>C

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.306T>C​(p.Asp102Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,612,084 control chromosomes in the GnomAD database, including 175,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17586 hom., cov: 33)
  • Exomes 𝑓: 0.46 (157837 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: -0.0840
• Publications: 41 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=-0.96).
• BP6: Variant 16-3254762-A-G is Benign according to our data. Variant chr16-3254762-A-G is described in ClinVar as Benign. ClinVar VariationId is 36509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.084 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.544 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.306T>C	p.Asp102Asp	synonymous	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+1549T>C		intron	N/A	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.306T>C	p.Asp102Asp	synonymous	Exon 2 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.277+1549T>C		intron	N/A	ENSP00000438711.1	O15553-3
	MEFV	ENST00000570511.5	TSL:1	n.306T>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71757 AN: 152018 Hom.: 17555 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.443 AC: 109255 AN: 246370 AF XY: 0.426

Gnomad AFR exome AF: 0.507

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.516

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.456 AC: 665515 AN: 1459948 Hom.: 157837 Cov.: 57 AF XY: 0.448 AC XY: 325088 AN XY: 726320

African (AFR) AF: 0.503 AC: 16823 AN: 33476

American (AMR) AF: 0.610 AC: 27268 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10527 AN: 26134

East Asian (EAS) AF: 0.147 AC: 5824 AN: 39698

South Asian (SAS) AF: 0.217 AC: 18744 AN: 86250

European-Finnish (FIN) AF: 0.506 AC: 26109 AN: 51604

Middle Eastern (MID) AF: 0.317 AC: 1827 AN: 5766

European-Non Finnish (NFE) AF: 0.479 AC: 532232 AN: 1111924

Other (OTH) AF: 0.433 AC: 26161 AN: 60376

GnomAD4 genome AF: 0.472 AC: 71845 AN: 152136 Hom.: 17586 Cov.: 33 AF XY: 0.469 AC XY: 34896 AN XY: 74380

African (AFR) AF: 0.506 AC: 20996 AN: 41486

American (AMR) AF: 0.554 AC: 8462 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1365 AN: 3472

East Asian (EAS) AF: 0.154 AC: 799 AN: 5180

South Asian (SAS) AF: 0.214 AC: 1032 AN: 4828

European-Finnish (FIN) AF: 0.514 AC: 5448 AN: 10592

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32301 AN: 67978

Other (OTH) AF: 0.464 AC: 978 AN: 2110

Alfa AF: 0.474 Hom.: 62790

Bravo AF: 0.481

Asia WGS AF: 0.240 AC: 839 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.459

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial Mediterranean fever (5)
-	-	5	not specified (5)
-	1	3	not provided (5)
-	-	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	-0.96
CADD	Benign	1.6
DANN	Benign	0.26
PhyloP100		-0.084
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: rs224225; hg19: chr16-3304762; COSMIC: COSV54819764;