15-48444487-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000138.5(FBN1):c.6037+54T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,604,964 control chromosomes in the GnomAD database, including 434,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34483 hom., cov: 32)

Exomes 𝑓: 0.74 ( 400211 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0670

Publications

13 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):

Marfan syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
familial thoracic aortic aneurysm and aortic dissection
Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Acromicric dysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
progeroid and marfanoid aspect-lipodystrophy syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
stiff skin syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

FBN1 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=-0.84).

BP6

Variant 15-48444487-A-T is Benign according to our data. Variant chr15-48444487-A-T is described in ClinVar as Benign. ClinVar VariationId is 1273419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. 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
	FBN1	NM_000138.5	MANE Select	c.6037+54T>A		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.6037+54T>A		intron	N/A	NP_001393645.1	P35555

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FBN1	ENST00000316623.10	TSL:1 MANE Select	c.6037+54T>A	intron	N/A	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6	TSL:1	n.6037+54T>A	intron	N/A	ENSP00000453958.2	H0YND0
FBN1	ENST00000684448.1		n.4765T>A	non_coding_transcript_exon	Exon 38 of 38

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

100588

AN:

151924

Hom.:

34487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.467

Gnomad AMI

AF:

0.565

Gnomad AMR

AF:

0.702

Gnomad ASJ

AF:

0.801

Gnomad EAS

AF:

0.598

Gnomad SAS

AF:

0.754

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.771

Gnomad NFE

AF:

0.752

Gnomad OTH

AF:

0.686

GnomAD4 exome

AF:

0.739

AC:

1074261

AN:

1452922

Hom.:

400211

AF XY:

0.742

AC XY:

536332

AN XY:

723256

show subpopulations

African (AFR)

AF:

0.449

AC:

14925

AN:

33254

American (AMR)

AF:

0.733

AC:

32656

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.789

AC:

20504

AN:

25990

East Asian (EAS)

AF:

0.576

AC:

22824

AN:

39592

South Asian (SAS)

AF:

0.776

AC:

66786

AN:

86046

European-Finnish (FIN)

AF:

0.726

AC:

38323

AN:

52764

Middle Eastern (MID)

AF:

0.714

AC:

4094

AN:

5736

European-Non Finnish (NFE)

AF:

0.752

AC:

830691

AN:

1104914

Other (OTH)

AF:

0.724

AC:

43458

AN:

60048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

13648

27295

40943

54590

68238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20072

40144

60216

80288

100360

<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:

0.662

AC:

100608

AN:

152042

Hom.:

34483

Cov.:

AF XY:

0.663

AC XY:

49272

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.466

AC:

19339

AN:

41464

American (AMR)

AF:

0.702

AC:

10718

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.801

AC:

2778

AN:

3468

East Asian (EAS)

AF:

0.596

AC:

3067

AN:

5144

South Asian (SAS)

AF:

0.754

AC:

3638

AN:

4824

European-Finnish (FIN)

AF:

0.735

AC:

7777

AN:

10582

Middle Eastern (MID)

AF:

0.771

AC:

225

AN:

292

European-Non Finnish (NFE)

AF:

0.752

AC:

51106

AN:

67976

Other (OTH)

AF:

0.687

AC:

1447

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1662

3324

4985

6647

8309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.699

Hom.:

4735

Bravo

AF:

0.649

Asia WGS

AF:

0.654

AC:

2274

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.62

(source)

DANN

Benign

0.51

PhyloP100

-0.067

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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