rs55649234

chr15-48448739-G-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000138.5(FBN1):c.5671+28_5671+29insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,604,668 control chromosomes in the GnomAD database, including 720 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (70 hom., cov: 32)
  • Exomes 𝑓: 0.022 (650 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.379

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 -16 ACMG points.

• BP6: Variant 15-48448739-G-GA is Benign according to our data. Variant chr15-48448739-G-GA is described in ClinVar as [Benign]. Clinvar id is 255301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.5671+28_5671+29insT		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.5671+28_5671+29insT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.5671+28_5671+29insT		intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3319 AN: 151960 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0834

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0260

GnomAD3 exomes AF: 0.0282 AC: 6956 AN: 246962 Hom.: 186 AF XY: 0.0268 AC XY: 3588 AN XY: 133722

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.0526

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0752

Gnomad SAS exome AF: 0.0399

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0218 AC: 31623 AN: 1452590 Hom.: 650 Cov.: 30 AF XY: 0.0220 AC XY: 15878 AN XY: 722882

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.0520

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0219 AC: 3325 AN: 152078 Hom.: 70 Cov.: 32 AF XY: 0.0231 AC XY: 1720 AN XY: 74316

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0836

Gnomad4 SAS AF: 0.0484

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.0257

Alfa AF: 0.0175 Hom.: 2

Bravo AF: 0.0233

Asia WGS AF: 0.0710 AC: 246 AN: 3476

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

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs55649234; hg19: chr15-48740936;