15-48444487-A-T

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.6037+54T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,604,964 control chromosomes in the GnomAD database, including 434,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34483 hom., cov: 32)
  • Exomes 𝑓: 0.74 (400211 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0670

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=-0.84).
• BP6: Variant 15-48444487-A-T is Benign according to our data. Variant chr15-48444487-A-T is described in ClinVar as [Benign]. Clinvar id is 1273419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48444487-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.6037+54T>A		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.6037+54T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.6037+54T>A		intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100588 AN: 151924 Hom.: 34487 Cov.: 32

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.686

GnomAD4 exome AF: 0.739 AC: 1074261 AN: 1452922 Hom.: 400211 AF XY: 0.742 AC XY: 536332 AN XY: 723256

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.733

Gnomad4 ASJ exome AF: 0.789

Gnomad4 EAS exome AF: 0.576

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.726

Gnomad4 NFE exome AF: 0.752

Gnomad4 OTH exome AF: 0.724

GnomAD4 genome AF: 0.662 AC: 100608 AN: 152042 Hom.: 34483 Cov.: 32 AF XY: 0.663 AC XY: 49272 AN XY: 74326

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.702

Gnomad4 ASJ AF: 0.801

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.754

Gnomad4 FIN AF: 0.735

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.687

Alfa AF: 0.699 Hom.: 4735

Bravo AF: 0.649

Asia WGS AF: 0.654 AC: 2274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

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	-0.84
Cadd	Benign	0.62
Dann	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs2303502; hg19: chr15-48736684; COSMIC: COSV57309625;