11-65868582-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016938.5(EFEMP2):c.775A>G(p.Ile259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,613,852 control chromosomes in the GnomAD database, including 781,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.91 ( 63941 hom., cov: 32)

Exomes 𝑓: 0.99 ( 717270 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 0.137

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.314085E-6).

BP6

Variant 11-65868582-T-C is Benign according to our data. Variant chr11-65868582-T-C is described in ClinVar as [Benign]. Clinvar id is 39015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65868582-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5 link	c.775A>G	p.Ile259Val	missense_variant	Exon 8 of 11	ENST00000307998.11	NP_058634.4	O95967A0A024R5G1Q9H3D5
EFEMP2	NR_037718.2 link	n.900A>G		non_coding_transcript_exon_variant	Exon 8 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11 link	c.775A>G	p.Ile259Val	missense_variant	Exon 8 of 11	1	NM_016938.5	ENSP00000309953.6		O95967

Frequencies

GnomAD3 genomes

AF:

0.906

AC:

137736

AN:

152094

Hom.:

63908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.678

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

0.955

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.925

GnomAD3 exomes

AF:

0.975

AC:

244922

AN:

251286

Hom.:

120160

AF XY:

0.982

AC XY:

133349

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.670

Gnomad AMR exome

AF:

0.981

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.999

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.987

GnomAD4 exome

AF:

0.989

AC:

1446057

AN:

1461640

Hom.:

717270

Cov.:

AF XY:

0.991

AC XY:

720498

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.664

Gnomad4 AMR exome

AF:

0.979

Gnomad4 ASJ exome

AF:

0.999

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.999

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.999

Gnomad4 OTH exome

AF:

0.976

GnomAD4 genome

AF:

0.905

AC:

137825

AN:

152212

Hom.:

63941

Cov.:

AF XY:

0.909

AC XY:

67608

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.678

Gnomad4 AMR

AF:

0.955

Gnomad4 ASJ

AF:

0.999

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.999

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.998

Gnomad4 OTH

AF:

0.926

Alfa

AF:

0.978

Hom.:

116884

Bravo

AF:

0.893

TwinsUK

AF:

0.999

AC:

3704

ALSPAC

AF:

0.998

AC:

3846

ESP6500AA

AF:

0.692

AC:

3044

ESP6500EA

AF:

0.998

AC:

8579

ExAC

AF:

0.969

AC:

117696

Asia WGS

AF:

0.984

AC:

3420

AN:

3478

EpiCase

AF:

0.998

EpiControl

AF:

0.997

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B

Benign:7

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2016

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile259Val in exon 8 of EFEMP2: This variant is not expected to have clinical sig nificance because it has been identified in 30.8% (1358/4402) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs601314). -

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The EFEMP2 c.775A>G (p.Ile259Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict benign outcome for this variant. This variant was found in 117556/121254 control chromosomes (57465 homozygotes) from ExAC at a frequency of 0.969502, which is approximately 8671 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), therefore allele G is the major allele at this position. Multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. Based on allele frequency of this variant in general population, this variant is classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Nov 17, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Cutis laxa, autosomal recessive, type 1A

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.1

DANN

Benign

0.77

DEOGEN2

Benign

0.0043

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0000043

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.38

.;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.68

N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.030

MPC

0.30

ClinPred

0.00071

GERP RS

1.9

Varity_R

0.020

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over