rs144320036

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 16/22 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.0220

Publications

6 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 -13 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 VariationId is 390442.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (156/152186) while in subpopulation NFE AF = 0.00177 (120/67986). AF 95% confidence interval is 0.00151. There are 2 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.139C>T	p.Pro47Ser	missense	Exon 3 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.264C>T		non_coding_transcript_exon	Exon 3 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.139C>T	p.Pro47Ser	missense	Exon 3 of 11	ENSP00000309953.6	O95967
EFEMP2	ENST00000531972.5	TSL:1	n.139C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000435295.1	O95967
EFEMP2	ENST00000907927.1		c.139C>T	p.Pro47Ser	missense	Exon 3 of 12	ENSP00000577986.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152068

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000971

AC:

152

AN:

156514

AF XY:

0.00107

show subpopulations

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 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.:

Cov.:

AF XY:

0.00103

AC XY:

710

AN XY:

690224

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31602

American (AMR)

AF:

0.000840

AC:

AN:

35712

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35746

South Asian (SAS)

AF:

0.000644

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

49232

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00109

AC:

1180

AN:

1078980

Other (OTH)

AF:

0.00105

AC:

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

182

272

363

454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00103

AC:

156

AN:

152186

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41504

American (AMR)

AF:

0.00137

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00177

AC:

120

AN:

67986

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00159

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000246

AC:

ESP6500EA

AF:

0.00138

AC:

ExAC

AF:

0.000483

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Cutis laxa, autosomal recessive, type 1B (3)

not specified (2)

Cardiovascular phenotype (1)

EFEMP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.055

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.022

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.86

PhyloP100

-0.022

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.21

Sift

Benign

0.25

Sift4G

Benign

0.61

Polyphen

0.022

Vest4

0.096

MVP

0.79

MPC

0.36

ClinPred

0.012

GERP RS

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.71

Mutation Taster

=97/3

polymorphism

(source)

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

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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