rs200285623

Positions:

• chr11-65868417-A-C
• chr11-65868417-A-G
• chr11-65868417-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016938.5(EFEMP2):​c.852T>G​(p.Ile284Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

Genes affected

EFEMP2 (HGNC:3219): (EGF containing fibulin extracellular matrix protein 2) A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.852T>G	p.Ile284Met	missense_variant	9/11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.977T>G		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.852T>G	p.Ile284Met	missense_variant	9/11	1	NM_016938.5	ENSP00000309953	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.83		Gain of disorder (P = 0.0362);Gain of disorder (P = 0.0362);
MVP		0.95
MPC		1.1
ClinPred		0.98	D
GERP RS		0.75
Varity_R		0.36
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs200285623; hg19: chr11-65635888;