rs2234462

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:13

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), Ambry Genetics, Genomics England PanelApp, ClinGen, G2P
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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016938.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	NM_016938.5	MANE Select	c.277G>A	p.Gly93Ser	missense	Exon 4 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.402G>A		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.277G>A	p.Gly93Ser	missense	Exon 4 of 11	ENSP00000309953.6	O95967
EFEMP2	ENST00000531972.5	TSL:1	n.277G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000435295.1	O95967
EFEMP2	ENST00000907927.1		c.277G>A	p.Gly93Ser	missense	Exon 4 of 12	ENSP00000577986.1

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cutis laxa, autosomal recessive, type 1B (5)

not provided (3)

not specified (3)

Cardiovascular phenotype (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.74

M_CAP

Benign

0.031

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PhyloP100

0.35

PrimateAI

Benign

0.38

PROVEAN

Benign

0.17

REVEL

Benign

0.16

Sift

Benign

0.41

Sift4G

Benign

0.76

Polyphen

0.026

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over