rs775257418

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000138.5(FBN1):c.2729-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.000080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBN1
NM_000138.5 splice_region, intron

Scores

Splicing: ADA: 0.00005031

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 15-48492594-G-A is Benign according to our data. Variant chr15-48492594-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 527226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.2729-8C>T		splice_region_variant, intron_variant	Intron 23 of 65	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.2729-8C>T		splice_region_variant, intron_variant	Intron 22 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.2729-8C>T		splice_region_variant, intron_variant	Intron 23 of 65	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.0000803

AC:

AN:

149462

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000811

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000629

AC:

143

AN:

227452

AF XY:

0.000525

show subpopulations

Gnomad AFR exome

AF:

0.000348

Gnomad AMR exome

AF:

0.000227

Gnomad ASJ exome

AF:

0.000756

Gnomad EAS exome

AF:

0.000366

Gnomad FIN exome

AF:

0.000672

Gnomad NFE exome

AF:

0.000786

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000149

AC:

210

AN:

1406438

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

105

AN XY:

701926

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000509

AC:

AN:

31434

American (AMR)

AF:

0.000693

AC:

AN:

41872

Ashkenazi Jewish (ASJ)

AF:

0.000276

AC:

AN:

25342

East Asian (EAS)

AF:

0.0000512

AC:

AN:

39062

South Asian (SAS)

AF:

0.000219

AC:

AN:

82212

European-Finnish (FIN)

AF:

0.000246

AC:

AN:

52816

Middle Eastern (MID)

AF:

0.000718

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.0000944

AC:

101

AN:

1069920

Other (OTH)

AF:

0.000344

AC:

AN:

58210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.248

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000803

AC:

AN:

149462

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72766

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000492

AC:

AN:

40690

American (AMR)

AF:

0.00

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.000811

AC:

AN:

9860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

67264

Other (OTH)

AF:

0.00

AC:

AN:

2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000194685), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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:

0.00684

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Sep 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.8

(source)

DANN

Benign

0.38

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000050

dbscSNV1_RF

Benign

0.016

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over