15-48555536-T-C

Variant names:

• chr15-48555536-T-C
• rs683282
• NM_000138.5:c.539-17728A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000138.5(FBN1):​c.539-17728A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 151,976 control chromosomes in the GnomAD database, including 22,468 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (22468 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

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.539-17728A>G		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.539-17728A>G		intron	N/A	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.539-17728A>G		intron	N/A	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.539-17728A>G		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.539-17728A>G		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.539-17728A>G		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73666 AN: 151858 Hom.: 22399 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.486 AC: 73796 AN: 151976 Hom.: 22468 Cov.: 32 AF XY: 0.483 AC XY: 35839 AN XY: 74260

African (AFR) AF: 0.865 AC: 35866 AN: 41476

American (AMR) AF: 0.392 AC: 5986 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 874 AN: 3462

East Asian (EAS) AF: 0.668 AC: 3444 AN: 5152

South Asian (SAS) AF: 0.336 AC: 1615 AN: 4812

European-Finnish (FIN) AF: 0.337 AC: 3550 AN: 10544

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.309 AC: 20979 AN: 67954

Other (OTH) AF: 0.449 AC: 947 AN: 2110

Alfa AF: 0.362 Hom.: 13814

Bravo AF: 0.509

Asia WGS AF: 0.566 AC: 1966 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs683282; hg19: chr15-48847733;