rs55694948

Positions:

• chr15-48465935-A-C
• chr15-48465935-A-G

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.4748-77T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 941,574 control chromosomes in the GnomAD database, including 12,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2660 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9962 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.306

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 15-48465935-A-C is Benign according to our data. Variant chr15-48465935-A-C is described in ClinVar as [Benign]. Clinvar id is 1237499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48465935-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4748-77T>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4748-77T>G		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4748-77T>G		intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27638 AN: 152022 Hom.: 2650 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.155 AC: 122496 AN: 789434 Hom.: 9962 AF XY: 0.155 AC XY: 64595 AN XY: 415952

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.182 AC: 27669 AN: 152140 Hom.: 2660 Cov.: 32 AF XY: 0.180 AC XY: 13387 AN XY: 74370

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.196

Alfa AF: 0.0822 Hom.: 106

Bravo AF: 0.188

Asia WGS AF: 0.239 AC: 828 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.37

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: rs55694948; hg19: chr15-48758132;