rs104895085

Variant names:

• chr16-3243529-C-A
• rs104895085
• NM_000243.3:c.1958G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3243529-C-A
• chr16-3243529-C-G
• chr16-3243529-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000243.3(MEFV):​c.1958G>T​(p.Arg653Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.522

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243529-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2876435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.1958G>T	p.Arg653Leu	missense_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*162G>T		3_prime_UTR_variant	Exon 9 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.1958G>T	p.Arg653Leu	missense_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44702

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26106

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39694

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53380

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1111830

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.29	N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.032	B;.;.
Vest4		0.17
MutPred		0.71		Loss of solvent accessibility (P = 0.0299);.;.;
MVP		0.55
MPC		0.16
ClinPred		0.14	T
GERP RS		1.6
Varity_R		0.45
gMVP		0.43

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: rs104895085; hg19: chr16-3293529;