chr15-48468542-C-T

Position:

chr15-48468542-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000138.5(FBN1):c.4460-8G>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 0.00000186 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FBN1
NM_000138.5 splice_region, intron

Scores

Splicing: ADA: 0.9994

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.547

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 links:

FBN1 (HGNC:):

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-48468542-C-T is Pathogenic according to our data. Variant chr15-48468542-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48468542-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.4460-8G>A		splice_region_variant, intron_variant		ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 linkuse as main transcript	c.4460-8G>A		splice_region_variant, intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.4460-8G>A		splice_region_variant, intron_variant		1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250992

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2019	The c.4460-8G>A variant in FBN1 has been reported in at least 3 individuals with Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Loeys 2001, Pepe 2007, Stheneur 2009). It has also been identified in 0.003% (1/34574) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 36075). This variant is located in the 3' splice region. Computational tools and in vitro splicing assays (Pepe 2007) predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting, PS4_Moderate. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Laboratory Medicine and Genetics, Samsung Medical Center	Jan 02, 2025	The NM_000138.5:c.4460-8G>A is considered to be not rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (SpliceAI). This variant was found in a patient with ectopia lentis or Marfan syndrome (PMID: 11700157; 18087243; 19293843; 32679894; 33844962; 38190127). This variant was found in a patient with Marfan syndrome meeting revised Ghent criteria (aortic root dilatation and ectopia lentis) (Samsung Medical Center internal data). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PS4, PP3, PP4 with weighted strength). -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been confirmed by reverse transcriptase PCR (RT-PCR) to activate a cryptic acceptor splice site resulting in an insertion of six intronic nucleotides in exon 36 (c.4459_4460insTTTTAG). The variant results in an in-frame insertion of two amino acids in the protein sequence, p.(Thr1486_Asp1487insValLeu) (PMID: 18087243). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable non canonical splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in >10 individuals with Marfan syndrome and ectopia lentis (ClinVar, PMID: 18087243, 11700157, 19293843, 32679894, doi:10.57204/001c.38690). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 18, 2024	This variant has been reported in the literature in at least 3 individuals who meet clinical diagnostic criteria for Marfan syndrome (MFS; Loeys 2001 PMID: 11700157; Stheneur 2009 PMID: 19293843; Stark 2020 PMID: 32679894), two unrelated individuals with ectopia lentis with or without additional systemic features of MFS and in at least two similarly affected family members (Pepe 2007 PMID: 18087243; Guo 2024 PMID: 38190127), and an individual with an undescribed clinical suspicion of MFS or another connective tissue disorder (Yoon 2023 PMID: 37558401). It is present in gnomAD (Highest reported MAF: 0.0017% [1/59992]; https://gnomad.broadinstitute.org/variant/15-48468542-C-T?dataset=gnomad_r4) and ClinVar (Variation ID: 36075). This variant is located in the acceptor splice region of intron 35, and is predicted to weaken the canonical acceptor site and create a new acceptor site two base pairs downstream from this variant. Complementary DNA (cDNA) sequencing studies are consistent with the in silico predictions, demonstrating that this variant results in the retention of the last 6 nucleotides of intron 35 into exon 35, which is predicted to result in the in-frame insertion of two novel amino acids (Loeys 2001 PMID: 11700157; Pepe 2007 PMID: 18087243). This predicted insertion p.(Thr1486_Asp1487insValLeu) would be in a calcium-binding EGF-like domain, positioned directly adjacent to that domain's consensus calcium-binding sequencing (Muiño-Mosquera 2018 PMID: 29875124). In summary, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); This single nucleotide substitution occurs upstream of the natural splice acceptor site in intron 36 and creates a new cryptic splice acceptor site. Two publications independently reported that cDNA sequence analysis demonstrated the result of this variant to be in-frame insertion of 6 nucleotides into the coding sequence (c.4459_4460insTTTTAG) (Loeys et al., 2001; Pepe et al., 2007).; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19293843, 18087243, 32679894, 11700157) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 07, 2022	- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 03, 2017

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2019

The c.4460-8G>A intronic variant results from a G to A substitution 8 nucleotides upstream from coding exon 36 in the FBN1 gene. This variant was reported in individuals with features of Marfan syndrome (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Loeys B et al. Hum. Mutat., 2004 Aug;24:140-6; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). In one family, this variant segregated with ectopia lentis in 3 relatives and RT-PCR analysis demonstrated an inframe insertion of 6 nucleotides due to use of a cryptic acceptor site (Pepe G et al. Mol. Vis., 2007 Nov;13:2242-7). Using four different splice site prediction tools, this alteration is predicted by ESEFinder, MaxEnt, and HSF to create a new alternate splice acceptor site, but BDGP does not predict the creation of a non-native acceptor site, nor a deleterious effect on splicing; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Based on data from gnomAD, the A allele has an overall frequency of approximately <0.001% (1/250992). This nucleotide position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

This sequence change falls in intron 36 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is present in population databases (rs193922204, gnomAD 0.003%). This variant has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 19293843; Invitae). This variant is also known as IVS35-8G>A. ClinVar contains an entry for this variant (Variation ID: 36075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Uncertain

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: -2

DS_AL_spliceai

0.33

Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over