rs104895175

Variant names:

• chr16-3254771-G-A
• rs104895175
• NM_000243.3:c.297C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3254771-G-A
• chr16-3254771-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_000243.3(MEFV):​c.297C>T​(p.Asn99Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,612,066 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: -0.600
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-3254771-G-A is Benign according to our data. Variant chr16-3254771-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97514.
• BP7: Synonymous conserved (PhyloP=-0.6 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.297C>T	p.Asn99Asn	synonymous	Exon 2 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.277+1540C>T		intron	N/A	NP_001185465.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.297C>T	p.Asn99Asn	synonymous	Exon 2 of 10	ENSP00000219596.1
	MEFV	ENST00000570511.5	TSL:1	n.297C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1
	MEFV	ENST00000541159.5	TSL:1	c.277+1540C>T		intron	N/A	ENSP00000438711.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152252 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000517 AC: 127 AN: 245544 AF XY: 0.000410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000249 AC: 363 AN: 1459814 Hom.: 2 Cov.: 34 AF XY: 0.000230 AC XY: 167 AN XY: 726260

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111976

Other (OTH) AF: 0.000795 AC: 48 AN: 60372

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68052

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000729 Hom.: 0

Bravo AF: 0.000332

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Familial Mediterranean fever (3)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial Mediterranean fever, autosomal dominant (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MEFV-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.78
DANN	Benign	0.35
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs104895175; hg19: chr16-3304771; COSMIC: COSV54818754;