rs104895094

Variant names:

• chr16-3243403-T-A
• rs104895094
• NM_000243.3:c.2084A>T
• MEFV p.Lys695Met

Your query was ambiguous. Multiple possible variants found:

• chr16-3243403-T-A
• chr16-3243403-T-C

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000243.3(MEFV):c.2084A>T (p.Lys695Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.K695N: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 97490) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K695= (synonymous): Likely_benign (ClinVar VariationId 2151614, 1 star); p.K695R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2547) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Familial mediterranean fever (fmf).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.429
• Publications: 194 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):

• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever

  Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Orphanet, ClinGen, Myriad Women's Health, PanelApp Australia
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_pathogenic. The variant received 6 points.

• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 3 benign (OR vs. background: 6.4).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00164) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.K695N: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 97490); Other variants at the same amino acid residue (not pathogenic): p.K695= (synonymous): Likely_benign (ClinVar VariationId 2151614, 1 star); p.K695R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2547)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	NM_000243.3	MANE Select	c.2084A>T	p.Lys695Met	missense	Exon 10 of 10	NP_000234.1	O15553-2
	MEFV	NM_001198536.2		c.*288A>T		3_prime_UTR	Exon 9 of 9	NP_001185465.2	O15553-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEFV	ENST00000219596.6	TSL:1 MANE Select	c.2084A>T	p.Lys695Met	missense	Exon 10 of 10	ENSP00000219596.1	O15553-2
	MEFV	ENST00000541159.5	TSL:1	c.*288A>T		3_prime_UTR	Exon 9 of 9	ENSP00000438711.1	O15553-3
	MEFV	ENST00000539145.5	TSL:1	n.*717A>T		3_prime_UTR	Exon 7 of 7	ENSP00000444471.1	D2DTW1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial Mediterranean fever (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.43
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.079	T
Sift4G	Uncertain	0.020	D
Varity_R		0.21
gMVP		0.38
Mutation Taster		=8/92	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104895094;

hg19: chr16-3293403;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar