rs119489102

Variant names:

• chr11-65868522-G-A
• rs119489102
• NM_016938.5:c.835C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_016938.5(EFEMP2):​c.835C>T​(p.Arg279Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,708 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002301387: Experimental studies have shown that this missense change affects EFEMP2 function (PMID:27339457)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.83
• 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), Ambry Genetics, Genomics England PanelApp, ClinGen, G2P
• 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002301387: Experimental studies have shown that this missense change affects EFEMP2 function (PMID: 27339457).; SCV002571764: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating decreased secretion in transfected mouse fibroblasts (Sasaki_2016)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 11-65868522-G-A is Pathogenic according to our data. Variant chr11-65868522-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	NM_016938.5	MANE Select	c.835C>T	p.Arg279Cys	missense	Exon 8 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.960C>T		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.835C>T	p.Arg279Cys	missense	Exon 8 of 11	ENSP00000309953.6	O95967
	EFEMP2	ENST00000527969.1	TSL:1	n.1520C>T		non_coding_transcript_exon	Exon 4 of 4
	EFEMP2	ENST00000531972.5	TSL:1	n.835C>T		non_coding_transcript_exon	Exon 8 of 12	ENSP00000435295.1	O95967

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

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: 0.0000252 AC: 1 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Cutis laxa, autosomal recessive, type 1B (3)
-	-	-	Cutis laxa, autosomal recessive, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.71		Gain of catalytic residue at L280 (P = 0.0153)
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.045	Neutral
Varity_R		0.90
gMVP		0.82
Mutation Taster		=54/46	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119489102; hg19: chr11-65635993; COSMIC: COSV57259720; COSMIC: COSV57259720;