rs140605

Positions:

• chr15-48497437-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.2168-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,553,576 control chromosomes in the GnomAD database, including 60,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10638 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50161 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.10

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=-0.9).
• BP6: Variant 15-48497437-T-C is Benign according to our data. Variant chr15-48497437-T-C is described in ClinVar as [Benign]. Clinvar id is 255288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48497437-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2168-46A>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2168-46A>G		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2168-46A>G		intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52382 AN: 151850 Hom.: 10610 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.279 AC: 67458 AN: 242142 Hom.: 10365 AF XY: 0.270 AC XY: 35538 AN XY: 131618

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.351

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.259 AC: 363291 AN: 1401608 Hom.: 50161 Cov.: 23 AF XY: 0.257 AC XY: 179881 AN XY: 700794

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.400

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.345 AC: 52465 AN: 151968 Hom.: 10638 Cov.: 32 AF XY: 0.343 AC XY: 25481 AN XY: 74278

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.319

Alfa AF: 0.287 Hom.: 1587

Bravo AF: 0.359

Asia WGS AF: 0.317 AC: 1103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 35. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.42
DANN	Benign	0.68

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: rs140605; hg19: chr15-48789634;