rs137854475

Variant names:

• chr15-48487155-C-T
• rs137854475
• NM_000138.5:c.3509G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-48487155-C-T
• chr15-48487155-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP2 BA1 BP5

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of 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: BA1, BP2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014215/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:7 B:27 O:1
• Conservation: PhyloP100: 2.10
• Publications: 28 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 -10 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.3509G>A	p.Arg1170His	missense	Exon 29 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3509G>A	p.Arg1170His	missense	Exon 28 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.3509G>A	p.Arg1170His	missense	Exon 29 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3509G>A		non_coding_transcript_exon	Exon 29 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3509G>A		non_coding_transcript_exon	Exon 29 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00126 AC: 316 AN: 251438 AF XY: 0.00133

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00245 AC: 3584 AN: 1461880 Hom.: 4 Cov.: 31 AF XY: 0.00241 AC XY: 1754 AN XY: 727244

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00303 AC: 3371 AN: 1112002

Other (OTH) AF: 0.00235 AC: 142 AN: 60396

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74454

African (AFR) AF: 0.000866 AC: 36 AN: 41554

American (AMR) AF: 0.00255 AC: 39 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00199 Hom.: 2

Bravo AF: 0.00219

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	3	6	Marfan syndrome (10)
-	1	6	not provided (7)
-	1	4	not specified (5)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	1	Acromicric dysplasia (1)
-	1	-	Disproportionate tall stature (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	FBN1-related disorder (1)
-	-	1	Geleophysic dysplasia (1)
-	1	-	Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	MASS syndrome (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)
-	-	-	Ectopia lentis;C0024796:Marfan syndrome;C0265313:Weill-Marchesani syndrome;C0345050:Congenital aneurysm of ascending aorta;C1858556:MASS syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.060
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.049	T
MetaSVM	Uncertain	-0.053	T
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Vest4		0.15
MVP		0.98
MPC		0.63
ClinPred		0.012	T
GERP RS		5.3
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs137854475; hg19: chr15-48779352; COSMIC: COSV57331178;