15-48520659-C-T

Variant names:

• chr15-48520659-C-T
• rs794728325
• NM_000138.5:c.1147G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PP2 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.1147G>A is a missense variant in FBN1 predicted to cause a substitution of a glutamic acid by lysine at amino acid 383 (p.Glu383Lys). This variant was found in a proband with a systemic score >7 and thoracic aortic aneurysm and/or dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 11700157, internal lab data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, once as likely pathogenic, and twice as uncertain significance (Variation ID: 200177). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant has been reported in the literature in at least three individuals with clinical features of MFS and/or thoracic aortic aneurysm and dissection (PS4_Mod; PMID 19159394, Invitae ClinVar entry, internal lab data) and in an individual with left iliac aneurysm (GeneDx internal lab data). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.702). This variant is located in the last nucleotide of exon 9. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM2_Sup, PP2, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011960/MONDO:0007947/022

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 7.73
• Publications: 5 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

Specifications for FBN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: 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.1147G>A	p.Glu383Lys	missense splice_region	Exon 10 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.1147G>A	p.Glu383Lys	missense splice_region	Exon 9 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.1147G>A	p.Glu383Lys	missense splice_region	Exon 10 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.1147G>A		splice_region non_coding_transcript_exon	Exon 10 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.1147G>A		splice_region non_coding_transcript_exon	Exon 10 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000779 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Marfan syndrome (2)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.30	D
PhyloP100		7.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.70
Sift	Benign	0.053	T
Sift4G	Uncertain	0.027	D
Vest4		0.85
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 0

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

Other links and lift over

dbSNP: rs794728325; hg19: chr15-48812856; COSMIC: COSV57313335;