chr15-48644711-T-C

Variant names:

• chr15-48644711-T-C
• rs201309310
• NM_000138.5:c.59A>G
• FBN1 p.Tyr20Cys

Variant summary

Our verdict is Uncertain significance. The variant received -5 ACMG points: 0P and 5B. BP2 BS1

This summary comes from the ClinGen Evidence Repository: The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016208/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:9 B:5 O:1
• Conservation: PhyloP100: 3.86
• Publications: 10 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Marfan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, Genomics England PanelApp
• 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: 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: Uncertain_significance. The variant received -5 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.59A>G	p.Tyr20Cys	missense	Exon 2 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.59A>G	p.Tyr20Cys	missense	Exon 1 of 65	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.59A>G	p.Tyr20Cys	missense	Exon 2 of 9	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.59A>G	p.Tyr20Cys	missense	Exon 2 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000560355.1	TSL:1	c.59A>G	p.Tyr20Cys	missense	Exon 2 of 2	ENSP00000453901.1	H0YN80
	FBN1	ENST00000559133.6	TSL:1	n.59A>G		non_coding_transcript_exon	Exon 2 of 67	ENSP00000453958.2	H0YND0

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251386 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000256 AC: 374 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.000231 AC XY: 168 AN XY: 727210

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53352

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

European-Non Finnish (NFE) AF: 0.000316 AC: 351 AN: 1112010

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (7)
1	1	2	Familial thoracic aortic aneurysm and aortic dissection (4)
-	2	-	Marfan syndrome (2)
-	1	1	not specified (2)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.83	T
PhyloP100		3.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.37
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201309310;

hg19: chr15-48936908;