chr11-65871247-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016938.5(EFEMP2):c.277G>A(p.Gly93Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,614,018 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G93G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 16 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.349

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

cutis laxa, autosomal recessive, type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
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

EFEMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036416352).

BP6

Variant 11-65871247-C-T is Benign according to our data. Variant chr11-65871247-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 424982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00332 (505/152272) while in subpopulation NFE AF = 0.00515 (350/68008). AF 95% confidence interval is 0.0047. There are 4 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5 link	c.277G>A	p.Gly93Ser	missense_variant	Exon 4 of 11	ENST00000307998.11	NP_058634.4	O95967A0A024R5G1Q9H3D5
EFEMP2	NR_037718.2 link	n.402G>A		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11 link	c.277G>A	p.Gly93Ser	missense_variant	Exon 4 of 11	1	NM_016938.5	ENSP00000309953.6		O95967

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00962

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00515

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00319

AC:

803

AN:

251426

AF XY:

0.00331

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0107

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00419

AC:

6122

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

3013

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33478

American (AMR)

AF:

0.000962

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00130

AC:

112

AN:

86248

European-Finnish (FIN)

AF:

0.0101

AC:

541

AN:

53412

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00464

AC:

5164

AN:

1111896

Other (OTH)

AF:

0.00353

AC:

213

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

387

773

1160

1546

1933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00332

AC:

505

AN:

152272

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41560

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00962

AC:

102

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00515

AC:

350

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00357

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00287

AC:

349

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B

Benign:5

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:3

Nov 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26017485) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EFEMP2: BP4, BS2 -

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.277G>A (p.Gly93Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 354/122264 control chromosomes including ExAC, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.009828 (65/6614). This frequency is about 88 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been found in multiple familial abdominal aortic aneurysm without evidence of segregation (van de Luijtgaarden_2015) and was classified as likely benign by the authors. One diagnostic laboratory has classified uncertain significance without evidence to independently evaluate. Taken together, this variant is classified as benign. -

not specified

Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP4;BP6 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

May 16, 2023

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

Jan 29, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0043

T;T;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

.;N;.;.

PhyloP100

0.35

PrimateAI

Benign

0.38

PROVEAN

Benign

0.17

N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.76

T;T;.;T

Polyphen

0.026

B;B;.;.

Vest4

0.15

MVP

0.56

MPC

0.35

ClinPred

0.0063

GERP RS

1.9

Varity_R

0.078

gMVP

0.38

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over