chr11-65868407-C-T

Variant names:

• chr11-65868407-C-T
• rs752273286
• NM_016938.5:c.862G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_016938.5(EFEMP2):​c.862G>A​(p.Glu288Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E288Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

EFEMP2 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal arteriopathy syndrome due to fibulin-4 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thoracic aortic aneurysm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016938.5. 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
	EFEMP2	NM_016938.5	MANE Select	c.862G>A	p.Glu288Lys	missense	Exon 9 of 11	NP_058634.4
	EFEMP2	NR_037718.2		n.987G>A		non_coding_transcript_exon	Exon 9 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.862G>A	p.Glu288Lys	missense	Exon 9 of 11	ENSP00000309953.6
	EFEMP2	ENST00000531972.5	TSL:1	n.862G>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000435295.1
	EFEMP2	ENST00000528176.5	TSL:5	c.862G>A	p.Glu288Lys	missense	Exon 9 of 11	ENSP00000434151.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251134 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.73
Sift	Benign	0.036	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.55		Gain of ubiquitination at E288 (P = 0.0128)
MVP		0.94
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		-0.0020	Neutral
Varity_R		0.49
gMVP		0.67
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs752273286; hg19: chr11-65635878;