NM_000243.3:c.495C>A

Variant names:

• chr16-3254573-G-T
• rs224223
• NM_000243.3:c.495C>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.495C>A​(p.Ala165Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,577,888 control chromosomes in the GnomAD database, including 169,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A165A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17488 hom., cov: 33)
  • Exomes 𝑓: 0.45 (152465 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 0.566
• Publications: 30 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=-0.84).
• BP6: Variant 16-3254573-G-T is Benign according to our data. Variant chr16-3254573-G-T is described in ClinVar as Benign. ClinVar VariationId is 36511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.566 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.545 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.495C>A	p.Ala165Ala	synonymous	Exon 2 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.277+1738C>A		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.495C>A	p.Ala165Ala	synonymous	Exon 2 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.277+1738C>A		intron	N/A	ENSP00000438711.1	O15553-3
	MEFV	ENST00000570511.5	TSL:1	n.495C>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1	I3L0S7

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71512 AN: 151942 Hom.: 17459 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.430 AC: 82493 AN: 191956 AF XY: 0.410

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.453 AC: 646049 AN: 1425828 Hom.: 152465 Cov.: 69 AF XY: 0.444 AC XY: 314359 AN XY: 707504

African (AFR) AF: 0.498 AC: 16313 AN: 32770

American (AMR) AF: 0.606 AC: 24195 AN: 39896

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10294 AN: 25570

East Asian (EAS) AF: 0.153 AC: 5841 AN: 38230

South Asian (SAS) AF: 0.195 AC: 16391 AN: 83996

European-Finnish (FIN) AF: 0.501 AC: 21752 AN: 43400

Middle Eastern (MID) AF: 0.322 AC: 1674 AN: 5196

European-Non Finnish (NFE) AF: 0.477 AC: 524067 AN: 1097740

Other (OTH) AF: 0.432 AC: 25522 AN: 59030

GnomAD4 genome AF: 0.471 AC: 71597 AN: 152060 Hom.: 17488 Cov.: 33 AF XY: 0.467 AC XY: 34729 AN XY: 74336

African (AFR) AF: 0.503 AC: 20885 AN: 41512

American (AMR) AF: 0.555 AC: 8487 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1365 AN: 3470

East Asian (EAS) AF: 0.162 AC: 830 AN: 5136

South Asian (SAS) AF: 0.191 AC: 924 AN: 4830

European-Finnish (FIN) AF: 0.514 AC: 5436 AN: 10576

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

European-Non Finnish (NFE) AF: 0.474 AC: 32225 AN: 67934

Other (OTH) AF: 0.464 AC: 980 AN: 2112

Alfa AF: 0.486 Hom.: 10677

Bravo AF: 0.480

Asia WGS AF: 0.233 AC: 814 AN: 3478

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	-0.84
CADD	Benign	2.9
DANN	Benign	0.64
PhyloP100		0.57
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: rs224223; hg19: chr16-3304573; COSMIC: COSV54818155;