15-48623687-T-C

Variant names:

• chr15-48623687-T-C
• rs2118181
• NM_000138.5:c.165-10595A>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.165-10595A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,102 control chromosomes in the GnomAD database, including 6,171 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 0.23 (6171 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54
• Publications: 24 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 = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.165-10595A>G		intron_variant	Intron 2 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.165-10595A>G		intron_variant	Intron 1 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.165-10595A>G		intron_variant	Intron 2 of 8		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.165-10595A>G		intron_variant	Intron 2 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.165-10595A>G		intron_variant	Intron 2 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.165-10595A>G		intron_variant	Intron 2 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.165-10595A>G		intron_variant	Intron 2 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34507 AN: 151984 Hom.: 6148 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.227 AC: 34584 AN: 152102 Hom.: 6171 Cov.: 32 AF XY: 0.223 AC XY: 16614 AN XY: 74350

African (AFR) AF: 0.499 AC: 20690 AN: 41434

American (AMR) AF: 0.175 AC: 2671 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3468

East Asian (EAS) AF: 0.274 AC: 1420 AN: 5178

South Asian (SAS) AF: 0.156 AC: 752 AN: 4820

European-Finnish (FIN) AF: 0.0711 AC: 754 AN: 10598

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7205 AN: 67996

Other (OTH) AF: 0.208 AC: 439 AN: 2114

Alfa AF: 0.144 Hom.: 2654

Bravo AF: 0.246

Asia WGS AF: 0.260 AC: 902 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.98
DANN	Benign	0.59
PhyloP100		-2.5
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: rs2118181; hg19: chr15-48915884;