rs141310608

Positions:

• chr11-65870222-C-A
• chr11-65870222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_016938.5(EFEMP2):​c.506G>T​(p.Arg169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R169H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-65870222-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.506G>T	p.Arg169Leu	missense_variant	6/11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.631G>T		non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.506G>T	p.Arg169Leu	missense_variant	6/11	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2021

The p.R169L variant (also known as c.506G>T), located in coding exon 5 of the EFEMP2 gene, results from a G to T substitution at nucleotide position 506. The arginine at codon 169 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.065	.;N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N;N;D;N
REVEL	Uncertain	0.61
Sift	Benign	0.054	T;D;D;D
Sift4G	Benign	0.17	T;T;.;T
Polyphen		0.99	D;P;.;.
Vest4		0.47
MutPred		0.62		Loss of disorder (P = 0.0499);Loss of disorder (P = 0.0499);Loss of disorder (P = 0.0499);Loss of disorder (P = 0.0499);
MVP		0.94
MPC		0.53
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs141310608; hg19: chr11-65637693; COSMIC: COSV57258775; COSMIC: COSV57258775;