rs756975501

chr16-3254608-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000243.3(MEFV):c.460T>C(p.Ser154Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000618 in 1,601,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S154S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09903842).
• BP6: Variant 16-3254608-A-G is Benign according to our data. Variant chr16-3254608-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234355.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.460T>C	p.Ser154Pro	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+1703T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.460T>C	p.Ser154Pro	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000391 AC: 9 AN: 229956 Hom.: 0 AF XY: 0.0000315 AC XY: 4 AN XY: 127066

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000587

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000635 AC: 92 AN: 1449516 Hom.: 0 Cov.: 62 AF XY: 0.0000555 AC XY: 40 AN XY: 720872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000932

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000677

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000334 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 154 of the MEFV protein (p.Ser154Pro). This variant is present in population databases (rs756975501, gnomAD 0.007%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 29260407, 31989427). ClinVar contains an entry for this variant (Variation ID: 234355). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	Identified with a second variant on the opposite allele (in trans) and as heterozygous with no second variant in individuals with Familial Mediterranean fever (Balta et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29260407, 31989427) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -

Familial Mediterranean fever, autosomal dominant Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 22, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 01, 2021

Variant summary: MEFV c.460T>C (p.Ser154Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 229956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460T>C has been reported in the literature in individuals affected with Familial Mediterranean Fever (Berdeli 2013, Balta 2018, Lane 2013, Martorana 2013, Rowczenio 2013) and also in a patient with primary immunodeficiency (Gallo 2016). These reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 13, 2021

- -

Acute febrile neutrophilic dermatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.75	D;D;D;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.18
Sift	Benign	0.076	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.15		Loss of phosphorylation at S154 (P = 0.0011);
MVP		0.68
MPC		0.15
ClinPred		0.051	T
GERP RS		3.4
Varity_R		0.073
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs756975501; hg19: chr16-3304608;