rs2228241

Variant names:

• chr15-48487353-G-A
• rs2228241
• NM_000138.5:c.3422C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS4

This summary comes from the ClinGen Evidence Repository: NM_00138 c.3422C>T is a missense variant in FBN1 predicted to cause a substitution of a Proline by Leucine at amino acid 1141 (p.Pro1141Leu). This variant has been reported in the literature in at least 3 individuals in association with thoracic aortic aneurysm and dissection (TAAD), MASS syndrome, and features possibly consistent with Marfan syndrome (PMID:10533071; PMID:24740214; PMID:26188975). This variant was also identified in an internal proband with isolated TAAD with a family history highly specific for Marfan syndrome, however it does not segregate with disease in an affected family member (BS4) and therefore PP4 cannot be used. This variant has been previously reported in ClinVar as benign, likely benign, and uncertain significance (Variation ID: 42334). This variant has been identified in 0.026% of individuals of European origin (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. 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 benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BS4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA014098/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:16
• Conservation: PhyloP100: 9.36
• Publications: 13 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: Benign. The variant received -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: 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.3422C>T	p.Pro1141Leu	missense	Exon 28 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3422C>T	p.Pro1141Leu	missense	Exon 27 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.3422C>T	p.Pro1141Leu	missense	Exon 28 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3422C>T		non_coding_transcript_exon	Exon 28 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3422C>T		non_coding_transcript_exon	Exon 28 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000903 AC: 227 AN: 251480 AF XY: 0.000846

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000508 AC: 742 AN: 1461884 Hom.: 4 Cov.: 32 AF XY: 0.000527 AC XY: 383 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 493 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000140 AC: 156 AN: 1112006

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74476

African (AFR) AF: 0.0000241 AC: 1 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000738 Hom.: 6

Bravo AF: 0.000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	1	3	Marfan syndrome (4)
-	-	2	not provided (2)
-	-	1	Acromicric dysplasia (1)
-	1	-	Developmental cataract (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.025	T
MetaSVM	Uncertain	0.58	D
PhyloP100		9.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.042	D
Vest4		0.70
MVP		0.81
MPC		1.4
ClinPred		0.28	T
GERP RS		5.6
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2228241; hg19: chr15-48779550;