15-48490366-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000138.5(FBN1):c.2855-288A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,000 control chromosomes in the GnomAD database, including 23,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.49 (23026 hom., cov: 31)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0380

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-48490366-T-C is Benign according to our data. Variant chr15-48490366-T-C is described in ClinVar as [Benign]. Clinvar id is 680570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.2855-288A>G		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.2855-288A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.2855-288A>G		intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74843 AN: 151882 Hom.: 22960 Cov.: 31

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.493 AC: 74972 AN: 152000 Hom.: 23026 Cov.: 31 AF XY: 0.491 AC XY: 36512 AN XY: 74290

Gnomad4 AFR AF: 0.867

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.724

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.455

Alfa AF: 0.327 Hom.: 11656

Bravo AF: 0.513

Asia WGS AF: 0.634 AC: 2202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.1
Dann	Benign	0.53

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: rs11635140; hg19: chr15-48782563;