NM_000138.5:c.6453C>T

Variant names:

• chr15-48437004-G-A
• rs794728251
• NM_000138.5:c.6453C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP3 PP4 PM2_Supporting PS3 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000138.5 c.6453C>T variant in FBN1does not result in an amino acid substitution. This variant was found in a proband with thoracic aortic aneurysm and/or dissection, and a systemic score of 8, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent university Hospital) (PP4). This variant has been reported 6 times in ClinVar: 4 times as pathogenic, 2 times as likely pathogenic, and once as variant of uncertain significance (Variation ID: 200193). The variant has been reported in the literature in at least two unrelated individuals with a clinical diagnosis of Marfan syndrome, and in at least four unrelated individuals with clinical features of Marfan syndrome (PMID 26787436, 36517271, 21907952, 32679894, 36517271, InvitaeClinVarentry) (PS4). This variant was also found to segregate with disease in at least 5 affected relatives from multiple families (PMID 21907952, internal data) (PP1_Strong). In silico prediction programs predict that this variant may impact splicing (PP3). RNA functional studies confirmed that this variant results in the creation of a cryptic donor splice site resulting in an abnormal truncated protein (PMID 21907952, 26787436, 32123317) (PS3). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS3, PS4, PP1_Strong, PM2_Sup, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016495/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 1.20
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.6453C>T	p.Cys2151Cys	synonymous	Exon 53 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.6453C>T	p.Cys2151Cys	synonymous	Exon 52 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.6453C>T	p.Cys2151Cys	synonymous	Exon 53 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.6453C>T		non_coding_transcript_exon	Exon 53 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.*2216C>T		non_coding_transcript_exon	Exon 28 of 31	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Marfan syndrome (4)
3	-	-	not provided (3)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.69
PhyloP100		1.2
Mutation Taster		=97/3	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: 2
DS_DL_spliceai		0.30		Position offset: -43

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

Other links and lift over

dbSNP: rs794728251; hg19: chr15-48729201; COSMIC: COSV57318600; COSMIC: COSV57318600;