rs144320036

chr11-65871991-G-Achr11-65871991-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016938.5(EFEMP2):c.139C>T(p.Pro47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,551,586 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (3 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.0220

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008275986).
• BP6: Variant 11-65871991-G-A is Benign according to our data. Variant chr11-65871991-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 390442.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}. Variant chr11-65871991-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5	c.139C>T	p.Pro47Ser	missense_variant	3/11	ENST00000307998.11
EFEMP2	NR_037718.2	n.264C>T		non_coding_transcript_exon_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11	c.139C>T	p.Pro47Ser	missense_variant	3/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152068 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000971 AC: 152 AN: 156514 Hom.: 0 AF XY: 0.00107 AC XY: 88 AN XY: 82346

Gnomad AFR exome AF: 0.000114

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000922

Gnomad FIN exome AF: 0.000130

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000968 AC: 1354 AN: 1399400 Hom.: 3 Cov.: 31 AF XY: 0.00103 AC XY: 710 AN XY: 690224

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000840

Gnomad4 ASJ exome AF: 0.000437

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000644

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00103 AC: 156 AN: 152186 Hom.: 2 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74408

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00177

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00164 Hom.: 1

Bravo AF: 0.00113

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000246 AC: 1

ESP6500EA AF: 0.00138 AC: 11

ExAC AF: 0.000483 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2022	This variant is associated with the following publications: (PMID: 27339457) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EFEMP2: BP4, BS2 -

Cutis laxa, autosomal recessive, type 1B Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The EFEMP2 c.139C>T; p.Pro47Ser variant (rs144320036), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 390442). This variant is found in the general population with an overall allele frequency of 0.104% (195/187,840 alleles) in the Genome Aggregation Database. The proline at codon 47 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.213). Due to limited information, the clinical significance of the p.Pro47Ser variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 19, 2023

Variant summary: EFEMP2 c.139C>T (p.Pro47Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 156514 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in EFEMP2 causing Autosomal Recessive Cutis Laxa phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.139C>T in individuals affected with Autosomal Recessive Cutis Laxa and no experimental evidence demonstrating its impact on protein function have been reported. At least one publication reports experimental evidence that this variant has no damaging effect on protein function (example: Sasaki_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27339457). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

EFEMP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.055	T;D;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.61	T;T;.;T
Polyphen		0.022	B;B;.;.
Vest4		0.096
MVP		0.79
MPC		0.36
ClinPred		0.012	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs144320036; hg19: chr11-65639462;