NM_000138.5:c.539-20652G>C

Variant names:

• chr15-48558460-C-G
• rs12441775
• NM_000138.5:c.539-20652G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000138.5(FBN1):​c.539-20652G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 152,104 control chromosomes in the GnomAD database, including 24,702 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 0.52 (24702 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277
• Publications: 1 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.539-20652G>C		intron_variant	Intron 6 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.539-20652G>C		intron_variant	Intron 5 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.539-20652G>C		intron_variant	Intron 6 of 8		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.539-20652G>C		intron_variant	Intron 6 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.539-20652G>C		intron_variant	Intron 6 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.539-20652G>C		intron_variant	Intron 6 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.539-20652G>C		intron_variant	Intron 6 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78444 AN: 151986 Hom.: 24711 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.561

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

GnomAD4 genome AF: 0.516 AC: 78430 AN: 152104 Hom.: 24702 Cov.: 32 AF XY: 0.519 AC XY: 38586 AN XY: 74356

African (AFR) AF: 0.134 AC: 5552 AN: 41506

American (AMR) AF: 0.608 AC: 9290 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2586 AN: 3472

East Asian (EAS) AF: 0.437 AC: 2260 AN: 5176

South Asian (SAS) AF: 0.631 AC: 3034 AN: 4812

European-Finnish (FIN) AF: 0.655 AC: 6925 AN: 10578

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 46937 AN: 67972

Other (OTH) AF: 0.556 AC: 1175 AN: 2112

Alfa AF: 0.587 Hom.: 3630

Bravo AF: 0.495

Asia WGS AF: 0.434 AC: 1511 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.28
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: rs12441775; hg19: chr15-48850657;