15-48446701-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):c.5788+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000253 in 1,578,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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: 0.0000021 ( 0 hom. )

Consequence

FBN1
NM_000138.5 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 6.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 15-48446701-C-T is Pathogenic according to our data. Variant chr15-48446701-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.5788+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000316623.10
FBN1	NM_001406716.1 linkuse as main transcript	c.5788+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.5788+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

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

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1426346

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

711940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

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:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:10

Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP1, PP4 and PM2, PS1, PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 also associated with causing Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; however some individuals have been reported with an autosomal recessive form of Marfan syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with the same variant reported in patients with a range of phenotypes (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR analysis of cultured fibroblasts from an affected individual showed that the variant causes in-frame skipping of exon 47 and a small amount of abnormally spliced transcripts utilized a cryptic splice donor or a cryptic splice acceptor (PMID: 7611299). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.5788+5G>T variant has been observed in an individual with Marfan syndrome and classified as likely pathogenic (VCGS laboratory). This variant has also been reported twice as a VUS in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome (ClinVar, PMID: 7611299, PMID: 24161884). (SP) 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 Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	case-control	deCODE genetics, Amgen	Apr 10, 2023	The c.5788+5G>A variant occurred de novo in two siblings (shared de novo) with Marfan syndrome, maternity and paternity confirmed, parental mosaicism assumed. Applied ACMG criteria: PS2, PM2, PP2, PP4, PP5_strong -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2014	The 5788+5G>A variant has been previously reported in >15 individuals with a cli nical diagnosis or features of Marfan syndrome, and was reported to have occurre d de novo in >10 of these individuals (Nijbroek 1995, Yuan 1999, Loeys 2001, Com eglio 2007, Rommel 2002, Biggin 2004, Arbustini 2005, Sakai 2006, Rand-Hendrikse n 2007, Stheneur 2009, Soylen 2009, Baetens 2011, Aalberts 2014, LMM unpublished data). This variant was absent from large population studies. This variant occu rs in the highly conserved 5' splicing consensus sequence. Nijbroek et al. (1995 ) observed skipping of exon 46 in fibroblasts from an affected individual with t his variant, which is predicted to result in an abnormal protein product. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 07, 2023	The c.5788+5G>A intronic variant in the FBN1 gene has been detected in heterozygous status including de novo occurrences in multiple unrelated individuals (>15) with classic Marfan syndrome features (PMID: 7611299, 11700157, 12402346, 8894692, 21542060, 16222657). Functional studies using RT-PCR performed on patient derived fibroblasts harboring this variant demonstrated in-frame skipping of the preceding exon 46 (117bp), resulting in aberrant protein product with deletion of 39 amino acids from the calcium-binding EGF-like domain of the fibrillin-1 protein (PMID: 7611299, 8894692). This variant is absent in the general population database gnomAD and is interpreted as pathogenic by several submitters in ClinVar database (ClinVar ID: 42394). Therefore, the c.5788+5G>A variant in FBN1 is classified as pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 31, 2020	The c.5788+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides downstream of coding exon 46 in the FBN1 gene. This mutation (also referred to as IVS 46+5G>A) was first described in three unrelated patients (two of whom were reported as de novo) with classic Marfan syndrome (MFS), and was shown to cause exon 46 skipping by mRNA analysis using cultured skin fibroblasts from one patient (Nijbroek G et al, Am. J. Hum. Genet. 1995 Jul; 57(1):8-21). This mutation has also been described in multiple additional patients with MFS with additional reported de novo occurrences (Loeys B et al, Arch. Intern. Med. 2001 Nov; 161(20):2447-54; Rommel K et al, Hum. Mutat. 2002 Nov; 20(5):406-7; Arbustini E et al, Hum. Mutat. 2005 Nov; 26(5):494; Sakai H et al, Am. J. Med. Genet. A 2006 Aug; 140(16):1719-25; Rand-Hendriksen S et al, Am. J. Med. Genet. A 2007 Sep; 143A(17):1968-77; Söylen B et al, Clin. Genet. 2009 Mar; 75(3):265-70; Baetens M et al, Hum. Mutat. 2011 Sep; 32(9):1053-62; Li J et al. Sci China Life Sci. 2019;62(12):1630-1637). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2022	Published functional studies showed RT-PCR performed on fibroblasts from individuals harboring this variant revealed c.5788+5 G>A leads to in-frame skipping of the preceding exon (Nijbroek et al., 1995; Lui et al., 1996; Wai et al., 2020).; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 42394; ClinVar); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 19293843, 11700157, 21542060, 14695540, 24161884, 8894692, 34818515, 34550612, 34498425, 7611299, 25525159, 17657824, 10533071, 12402346, 16835936, 17663468, 19159394, 33174221, 33083483, 31098894, 31730815, 16220557, 32123317, 16222657, 26582918) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Arachnodactyly;C0012736:Dissecting aortic dilatation;C0013581:Ectopia lentis;C0025202:Melanoma;C0271183:High myopia;C0948008:Ischemic stroke;C1298820:Aortic root aneurysm

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 25, 2016

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PS2,PM2,PP3,PP5 -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 16, 2023

Variant summary: FBN1 c.5788+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predicts the variant weakens the canonical 5' splicing donor site. Two publications report experimental evidence suggesting that this variant causes skipping of exon 46 (Liu_1996; Nijbroek_1995). The variant was absent in 251390 control chromosomes. c.5788+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (example, Baetens_2011, Liu_1996, Nijbroek_1995, Rand-Hendriksen_2007, Stheneur_2009). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

FBN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The FBN1 c.5788+5G>A variant is predicted to interfere with splicing. This variant has been reported in many affected individuals in the FBN1 mutation database (http://www.umd.be/FBN1/) and is documented as pathogenic for Marfan syndrome (Liu et al. 1996. PubMed ID: 8894692; Nijbroek et al. 1995. PubMed ID: 7611299; Yuan et al. 1999. PubMed ID: 10533071; Table S1, Li et al. 2019. PubMed ID: 31098894; Mannucci et al. 2020. PubMed ID: 31730815). The c.5788+5G>A has been shown to result in exon skipping in patient-derived skin fibroblasts (Nijbroek et al. 1995. PubMed ID: 7611299; Liu et al. 1996. PubMed ID: 8894692). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

This sequence change falls in intron 47 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 7611299, 11700157, 12402346, 14695540, 17657824, 17663468). In at least one individual the variant was observed to be de novo. This variant is also known as IVS46+5G>A. ClinVar contains an entry for this variant (Variation ID: 42394). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 46, but is expected to preserve the integrity of the reading-frame (PMID: 7611299). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.15

Cadd

Pathogenic

Dann

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.47

Position offset: -28

DS_DL_spliceai

0.35

Position offset: 5

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