ENST00000541159.5:c.1306G>A

Variant names:

• chr16-3243888-C-T
• rs1231122
• ENST00000541159.5:c.1306G>A
• MEFV p.Gly436Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000541159.5(MEFV):​c.1306G>A​(p.Gly436Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,612,752 control chromosomes in the GnomAD database, including 153,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12998 hom., cov: 31)
  • Exomes 𝑓: 0.43 (140598 hom.)
• Consequence: MEFV ENST00000541159.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.206
• 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):

• 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 (MetaRNN=6.046295E-4).
• BP6: Variant 16-3243888-C-T is Benign according to our data. Variant chr16-3243888-C-T is described in ClinVar as Benign. ClinVar VariationId is 36505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541159.5. 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.1764G>A	p.Pro588Pro	synonymous	Exon 9 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.1306G>A	p.Gly436Arg	missense	Exon 8 of 9	NP_001185465.2	O15553-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000541159.5	TSL:1	c.1306G>A	p.Gly436Arg	missense	Exon 8 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1764G>A	p.Pro588Pro	synonymous	Exon 9 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000539145.5	TSL:1	n.*397G>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62069 AN: 151778 Hom.: 12999 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.426

GnomAD2 exomes AF: 0.392 AC: 98072 AN: 250496 AF XY: 0.396

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.429

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.431

GnomAD4 exome AF: 0.434 AC: 634285 AN: 1460856 Hom.: 140598 Cov.: 57 AF XY: 0.432 AC XY: 313647 AN XY: 726710

African (AFR) AF: 0.333 AC: 11130 AN: 33468

American (AMR) AF: 0.272 AC: 12164 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11508 AN: 26136

East Asian (EAS) AF: 0.386 AC: 15331 AN: 39696

South Asian (SAS) AF: 0.286 AC: 24670 AN: 86230

European-Finnish (FIN) AF: 0.436 AC: 23214 AN: 53230

Middle Eastern (MID) AF: 0.442 AC: 2548 AN: 5768

European-Non Finnish (NFE) AF: 0.457 AC: 507896 AN: 1111288

Other (OTH) AF: 0.428 AC: 25824 AN: 60366

GnomAD4 genome AF: 0.409 AC: 62086 AN: 151896 Hom.: 12998 Cov.: 31 AF XY: 0.404 AC XY: 30014 AN XY: 74204

African (AFR) AF: 0.338 AC: 13983 AN: 41414

American (AMR) AF: 0.375 AC: 5723 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1511 AN: 3468

East Asian (EAS) AF: 0.388 AC: 1995 AN: 5148

South Asian (SAS) AF: 0.272 AC: 1313 AN: 4824

European-Finnish (FIN) AF: 0.442 AC: 4652 AN: 10520

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.461 AC: 31326 AN: 67952

Other (OTH) AF: 0.424 AC: 893 AN: 2106

Alfa AF: 0.438 Hom.: 40777

Bravo AF: 0.400

Asia WGS AF: 0.307 AC: 1068 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	10
DANN	Benign	0.28
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.00060	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.21
PROVEAN	Benign	1.7	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1231122;

hg19: chr16-3293888;

COSMIC: COSV54819435;

COSMIC: COSV54819435;