rs2234462

Positions:

chr11-65871247-C-T

Variant summary

Our verdict is Benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:11

Conservation

PhyloP100: 0.349

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=0.0036416352).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11 link	c.277G>A	p.Gly93Ser	missense_variant	4/11	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

GnomAD3 exomes

AF:

0.00319

AC:

803

AN:

251426

Hom.:

AF XY:

0.00331

AC XY:

450

AN XY:

135914

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 SAS exome

AF:

0.00118

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

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.00464

Gnomad4 OTH exome

AF:

0.00353

GnomAD4 genome

AF:

0.00332

AC:

505

AN:

152272

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00962

Gnomad4 NFE

AF:

0.00515

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00362

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EFEMP2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2018	This variant is associated with the following publications: (PMID: 26017485) -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2019

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

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;.;.

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

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

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