15-48468553-T-C

Position:

• chr15-48468553-T-C

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.4460-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,552 control chromosomes in the GnomAD database, including 599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (55 hom., cov: 32)
  • Exomes 𝑓: 0.015 (544 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.458

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-48468553-T-C is Benign according to our data. Variant chr15-48468553-T-C is described in ClinVar as [Benign]. Clinvar id is 137308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48468553-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4460-19A>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4460-19A>G		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4460-19A>G		intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2673 AN: 151984 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.0836

Gnomad SAS AF: 0.0473

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.0212

GnomAD3 exomes AF: 0.0248 AC: 6222 AN: 250842 Hom.: 176 AF XY: 0.0238 AC XY: 3225 AN XY: 135562

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0511

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0763

Gnomad SAS exome AF: 0.0400

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0153 AC: 22358 AN: 1461450 Hom.: 544 Cov.: 32 AF XY: 0.0158 AC XY: 11452 AN XY: 727034

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0505

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00899

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0176 AC: 2679 AN: 152102 Hom.: 55 Cov.: 32 AF XY: 0.0191 AC XY: 1420 AN XY: 74328

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0318

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.0838

Gnomad4 SAS AF: 0.0478

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.00957

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0130 Hom.: 2

Bravo AF: 0.0193

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.27

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: rs55840194; hg19: chr15-48760750;