16-3254411-G-C

Variant names:

• chr16-3254411-G-C
• rs104895182
• NM_000243.3:c.657C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000243.3(MEFV):​c.657C>G​(p.Gly219Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G219G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEFV NM_000243.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.628
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-3254411-G-C is Benign according to our data. Variant chr16-3254411-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2883169.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.628 with no splicing effect.

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.657C>G	p.Gly219Gly	synonymous	Exon 2 of 10	NP_000234.1
	MEFV	NM_001198536.2		c.277+1900C>G		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.657C>G	p.Gly219Gly	synonymous	Exon 2 of 10	ENSP00000219596.1
	MEFV	ENST00000570511.5	TSL:1	n.657C>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000458312.1
	MEFV	ENST00000541159.5	TSL:1	c.277+1900C>G		intron	N/A	ENSP00000438711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000357 AC: 84 AN: 235542 AF XY: 0.000262

Gnomad AFR exome AF: 0.000792

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.000625

Gnomad FIN exome AF: 0.000793

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000346

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000364 AC: 53 AN: 1456344 Hom.: 0 Cov.: 32 AF XY: 0.0000414 AC XY: 30 AN XY: 724282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33374

American (AMR) AF: 0.000114 AC: 5 AN: 43834

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26068

East Asian (EAS) AF: 0.000255 AC: 10 AN: 39282

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86010

European-Finnish (FIN) AF: 0.000430 AC: 22 AN: 51220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1110832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial Mediterranean fever Benign:1

May 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.46
PhyloP100		-0.63

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: rs104895182; hg19: chr16-3304411;