rs77380520

Variant names:

• chr16-3244246-G-A
• rs77380520
• NM_000243.3:c.1759+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3244246-G-A
• chr16-3244246-G-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.1759+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,613,954 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (245 hom.)
• Consequence: MEFV NM_000243.3 splice_region, intron
• Scores: Splicing: ADA: 0.000007063
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -1.76
• Publications: 10 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=-0.92).
• BP6: Variant 16-3244246-G-A is Benign according to our data. Variant chr16-3244246-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0939 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.1759+8C>T		splice_region intron	N/A	NP_000234.1
	MEFV	NM_001198536.2		c.1126+8C>T		splice_region intron	N/A	NP_001185465.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.1759+8C>T		splice_region intron	N/A	ENSP00000219596.1
	MEFV	ENST00000541159.5	TSL:1	c.1126+8C>T		splice_region intron	N/A	ENSP00000438711.1
	MEFV	ENST00000539145.5	TSL:1	n.*392+8C>T		splice_region intron	N/A	ENSP00000444471.1

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 703 AN: 151990 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00816

GnomAD2 exomes AF: 0.00930 AC: 2337 AN: 251346 AF XY: 0.00935

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00368 AC: 5377 AN: 1461846 Hom.: 245 Cov.: 36 AF XY: 0.00391 AC XY: 2843 AN XY: 727218

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0877 AC: 3480 AN: 39698

South Asian (SAS) AF: 0.0119 AC: 1024 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1111998

Other (OTH) AF: 0.0104 AC: 628 AN: 60396

GnomAD4 genome AF: 0.00462 AC: 702 AN: 152108 Hom.: 25 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74356

African (AFR) AF: 0.00108 AC: 45 AN: 41502

American (AMR) AF: 0.00164 AC: 25 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.101 AC: 523 AN: 5176

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68000

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.000462 Hom.: 0

Bravo AF: 0.00493

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial Mediterranean fever (6)
-	-	2	not specified (2)
-	-	1	Acute febrile neutrophilic dermatosis (1)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.54
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs77380520; hg19: chr16-3294246;