rs77105137

Positions:

• chr15-48463275-G-A

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.5066-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 1,604,986 control chromosomes in the GnomAD database, including 6,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.073 (453 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5822 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.600

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: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-48463275-G-A is Benign according to our data. Variant chr15-48463275-G-A is described in ClinVar as [Benign]. Clinvar id is 255299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48463275-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5066-35C>T		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5066-35C>T		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5066-35C>T		intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11176 AN: 152062 Hom.: 452 Cov.: 33

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.0856

GnomAD3 exomes AF: 0.0704 AC: 17666 AN: 251012 Hom.: 823 AF XY: 0.0719 AC XY: 9759 AN XY: 135666

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0373

Gnomad FIN exome AF: 0.0640

Gnomad NFE exome AF: 0.0939

Gnomad OTH exome AF: 0.0907

GnomAD4 exome AF: 0.0846 AC: 122844 AN: 1452806 Hom.: 5822 Cov.: 30 AF XY: 0.0838 AC XY: 60588 AN XY: 723326

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0383

Gnomad4 FIN exome AF: 0.0650

Gnomad4 NFE exome AF: 0.0930

Gnomad4 OTH exome AF: 0.0856

GnomAD4 genome AF: 0.0734 AC: 11176 AN: 152180 Hom.: 453 Cov.: 33 AF XY: 0.0715 AC XY: 5319 AN XY: 74408

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.0901

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0383

Gnomad4 FIN AF: 0.0610

Gnomad4 NFE AF: 0.0945

Gnomad4 OTH AF: 0.0843

Alfa AF: 0.0912 Hom.: 126

Bravo AF: 0.0735

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2017	Variant summary: The FBN1 c.5066-35C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19408/276744 control chromosomes at a frequency of 0.0701298, which is approximately 623 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), indicating this variant is a benign polymorphism. In addition, a clinical diagnostic laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 19, 2018	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.52
BranchPoint Hunter		2.0

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: rs77105137; hg19: chr15-48755472; COSMIC: COSV57315200;