15-48448739-GA-GAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000138.5(FBN1):c.5671+28dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,604,668 control chromosomes in the GnomAD database, including 720 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 70 hom., cov: 32)

Exomes 𝑓: 0.022 ( 650 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.379

Publications

2 publications found

Variant links:

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Marfan syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
Acromicric dysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
progeroid and marfanoid aspect-lipodystrophy syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
stiff skin syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Weill-Marchesani syndrome 2, dominant
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
geleophysic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated ectopia lentis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neonatal Marfan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Weill-Marchesani syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ectopia lentis 1, isolated, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: G2P
Shprintzen-Goldberg syndrome
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 15-48448739-G-GA is Benign according to our data. Variant chr15-48448739-G-GA is described in ClinVar as Benign. ClinVar VariationId is 255301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.5671+28dupT		intron_variant	Intron 46 of 65	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.5671+28dupT		intron_variant	Intron 45 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.5671+28_5671+29insT		intron_variant	Intron 46 of 65	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3319

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0834

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0164

Gnomad OTH

AF:

0.0260

GnomAD2 exomes

AF:

0.0282

AC:

6956

AN:

246962

AF XY:

0.0268

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.0526

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0752

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0310

GnomAD4 exome

AF:

0.0218

AC:

31623

AN:

1452590

Hom.:

650

Cov.:

AF XY:

0.0220

AC XY:

15878

AN XY:

722882

show subpopulations

African (AFR)

AF:

0.0141

AC:

468

AN:

33262

American (AMR)

AF:

0.0520

AC:

2314

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

414

AN:

25982

East Asian (EAS)

AF:

0.110

AC:

4313

AN:

39338

South Asian (SAS)

AF:

0.0355

AC:

3037

AN:

85634

European-Finnish (FIN)

AF:

0.0146

AC:

754

AN:

51752

Middle Eastern (MID)

AF:

0.0254

AC:

146

AN:

5738

European-Non Finnish (NFE)

AF:

0.0168

AC:

18582

AN:

1106448

Other (OTH)

AF:

0.0266

AC:

1595

AN:

59952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1377

2754

4130

5507

6884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

834

1668

2502

3336

4170

<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:

0.0219

AC:

3325

AN:

152078

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1720

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0153

AC:

633

AN:

41494

American (AMR)

AF:

0.0349

AC:

533

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.0836

AC:

433

AN:

5180

South Asian (SAS)

AF:

0.0484

AC:

233

AN:

4814

European-Finnish (FIN)

AF:

0.0174

AC:

183

AN:

10546

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0164

AC:

1115

AN:

67986

Other (OTH)

AF:

0.0257

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0175

Hom.:

Bravo

AF:

0.0233

Asia WGS

AF:

0.0710

AC:

246

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over