rs111550973

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.368-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,956 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 12 hom. )

Consequence

EFEMP2
NM_016938.5 splice_region, intron

Scores

Splicing: ADA: 0.00002104

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.98

Publications

2 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 (BayesDel_noAF=-0.7).

BP6

Variant 11-65870662-C-T is Benign according to our data. Variant chr11-65870662-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226628.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 = 0.00209 (318/152266) while in subpopulation NFE AF = 0.00393 (267/68012). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 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.368-4G>A		splice_region intron	N/A	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.493-4G>A		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.368-4G>A	splice_region intron	N/A	ENSP00000309953.6	O95967
EFEMP2	ENST00000527969.1	TSL:1	n.47-4G>A	splice_region intron	N/A
EFEMP2	ENST00000531972.5	TSL:1	n.368-4G>A	splice_region intron	N/A	ENSP00000435295.1	O95967

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00393

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00168

AC:

422

AN:

250690

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.000679

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000372

Gnomad NFE exome

AF:

0.00333

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00323

AC:

4728

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

2270

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33478

American (AMR)

AF:

0.000335

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000638

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00410

AC:

4561

AN:

1111992

Other (OTH)

AF:

0.00156

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

284

568

853

1137

1421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.00209

AC:

318

AN:

152266

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41542

American (AMR)

AF:

0.000327

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00393

AC:

267

AN:

68012

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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:

0.00264

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.000289

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 (4)

Cardiovascular phenotype (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.36

(source)

DANN

Benign

0.90

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.050

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