chr11-65869905-G-A

Variant names:

• chr11-65869905-G-A
• rs397514683
• NM_016938.5:c.679C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_016938.5(EFEMP2):​c.679C>T​(p.Arg227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,736 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.98
• Publications: 8 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 11-65869905-G-A is Pathogenic according to our data. Variant chr11-65869905-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 42041.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.804C>T		non_coding_transcript_exon_variant	Exon 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 11	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727170

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Pathogenic:2

Sep 03, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.68		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.96
MPC		1.3
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.82
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs397514683; hg19: chr11-65637376; COSMIC: COSV57260968; COSMIC: COSV57260968;