rs363800

Positions:

• chr15-48446885-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.5672-63G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,144,726 control chromosomes in the GnomAD database, including 629 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (68 hom., cov: 32)
  • Exomes 𝑓: 0.023 (561 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-48446885-C-A is Benign according to our data. Variant chr15-48446885-C-A is described in ClinVar as [Benign]. Clinvar id is 1286477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48446885-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.5672-63G>T		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.5672-63G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.5672-63G>T		intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3309 AN: 152100 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.0477

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0264

GnomAD4 exome AF: 0.0233 AC: 23173 AN: 992508 Hom.: 561 AF XY: 0.0234 AC XY: 12058 AN XY: 515016

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.0524

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0352

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0262

GnomAD4 genome AF: 0.0218 AC: 3315 AN: 152218 Hom.: 68 Cov.: 32 AF XY: 0.0230 AC XY: 1711 AN XY: 74416

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0827

Gnomad4 SAS AF: 0.0481

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0171 Hom.: 0

Bravo AF: 0.0234

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 12, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs363800; hg19: chr15-48739082;