15-48534224-CAGAG-CAG

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.737-21_737-20delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,574,630 control chromosomes in the GnomAD database, including 402 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 209 hom., cov: 32)

Exomes 𝑓: 0.011 ( 193 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.707

Publications

3 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 15-48534224-CAG-C is Benign according to our data. Variant chr15-48534224-CAG-C is described in ClinVar as Benign. ClinVar VariationId is 255309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FBN1	NM_000138.5	MANE Select	c.737-21_737-20delCT	intron	N/A	NP_000129.3
FBN1	NM_001406716.1		c.737-21_737-20delCT	intron	N/A	NP_001393645.1
FBN1	NM_001406717.1		c.737-21_737-20delCT	intron	N/A	NP_001393646.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FBN1	ENST00000316623.10	TSL:1 MANE Select	c.737-21_737-20delCT	intron	N/A	ENSP00000325527.5
FBN1	ENST00000559133.6	TSL:1	n.737-21_737-20delCT	intron	N/A	ENSP00000453958.2
FBN1	ENST00000537463.6	TSL:5	n.636+3485_636+3486delCT	intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3476

AN:

145364

Hom.:

207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0332

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0482

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.241

Gnomad SAS

AF:

0.0202

Gnomad FIN

AF:

0.00394

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.0238

GnomAD2 exomes

AF:

0.0296

AC:

6584

AN:

222242

AF XY:

0.0260

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.0686

Gnomad ASJ exome

AF:

0.000769

Gnomad EAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0108

AC:

15398

AN:

1429160

Hom.:

193

AF XY:

0.0105

AC XY:

7473

AN XY:

710674

show subpopulations

African (AFR)

AF:

0.0291

AC:

919

AN:

31550

American (AMR)

AF:

0.0650

AC:

2569

AN:

39512

Ashkenazi Jewish (ASJ)

AF:

0.000875

AC:

AN:

25156

East Asian (EAS)

AF:

0.225

AC:

8612

AN:

38340

South Asian (SAS)

AF:

0.0151

AC:

1222

AN:

81168

European-Finnish (FIN)

AF:

0.00315

AC:

157

AN:

49898

Middle Eastern (MID)

AF:

0.00410

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.000749

AC:

823

AN:

1099172

Other (OTH)

AF:

0.0179

AC:

1051

AN:

58756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

556

1112

1669

2225

2781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.0240

AC:

3493

AN:

145470

Hom.:

209

Cov.:

AF XY:

0.0261

AC XY:

1844

AN XY:

70522

show subpopulations

African (AFR)

AF:

0.0333

AC:

1333

AN:

39974

American (AMR)

AF:

0.0485

AC:

710

AN:

14638

Ashkenazi Jewish (ASJ)

AF:

0.000292

AC:

AN:

3430

East Asian (EAS)

AF:

0.241

AC:

1204

AN:

4994

South Asian (SAS)

AF:

0.0200

AC:

AN:

4544

European-Finnish (FIN)

AF:

0.00394

AC:

AN:

8890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

65880

Other (OTH)

AF:

0.0245

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00240

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FBN1 c.737-21_737-20delCT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.03 in 222242 control chromosomes in the gnomAD database, including 47 homozygotes. The observed variant frequency is approximately 263- fold the estimated maximal allele frequency expected for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.737-21_737-20delCT in individuals affected with Aortopathy and no experimental evidence demonstrating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

not provided

Benign:2

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.71

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over