NM_000138.5:c.538+24113T>C

Variant names:

• chr15-48572170-A-G
• rs682938
• NM_000138.5:c.538+24113T>C

Variant summary

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

The NM_000138.5(FBN1):​c.538+24113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 151,996 control chromosomes in the GnomAD database, including 20,742 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 0.47 (20742 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.538+24113T>C		intron_variant	Intron 6 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.538+24113T>C		intron_variant	Intron 5 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.538+24113T>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.538+24113T>C		intron_variant	Intron 6 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.538+24113T>C		intron_variant	Intron 6 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.538+24113T>C		intron_variant	Intron 6 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.538+24113T>C		intron_variant	Intron 6 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71037 AN: 151878 Hom.: 20680 Cov.: 32

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.468 AC: 71164 AN: 151996 Hom.: 20742 Cov.: 32 AF XY: 0.464 AC XY: 34504 AN XY: 74292

African (AFR) AF: 0.835 AC: 34650 AN: 41486

American (AMR) AF: 0.385 AC: 5874 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2693 AN: 5164

South Asian (SAS) AF: 0.322 AC: 1551 AN: 4820

European-Finnish (FIN) AF: 0.336 AC: 3534 AN: 10532

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20577 AN: 67938

Other (OTH) AF: 0.432 AC: 910 AN: 2108

Alfa AF: 0.367 Hom.: 4189

Bravo AF: 0.489

Asia WGS AF: 0.498 AC: 1722 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.69
PhyloP100		-0.060
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: rs682938; hg19: chr15-48864367;