rs766531680

Variant names:

• chr11-65870133-G-A
• rs766531680
• NM_016938.5:c.595C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-65870133-G-A
• chr11-65870133-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016938.5(EFEMP2):​c.595C>T​(p.Arg199Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,464 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. R199S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• 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), 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

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.595C>T	p.Arg199Cys	missense	Exon 6 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.720C>T		non_coding_transcript_exon	Exon 6 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.595C>T	p.Arg199Cys	missense	Exon 6 of 11	ENSP00000309953.6	O95967
	EFEMP2	ENST00000527969.1	TSL:1	n.572C>T		non_coding_transcript_exon	Exon 2 of 4
	EFEMP2	ENST00000531972.5	TSL:1	n.595C>T		non_coding_transcript_exon	Exon 6 of 12	ENSP00000435295.1	O95967

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250324 AF XY: 0.0000147

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461464 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.81
Mutation Taster		=55/45	polymorphism

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: rs766531680; hg19: chr11-65637604;