rs17364665

Positions:

• chr15-48592632-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000138.5(FBN1):​c.538+3651T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 152,248 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.052 (264 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.538+3651T>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.538+3651T>G		intron_variant			NP_001393645.1
FBN1	NM_001406717.1	c.538+3651T>G		intron_variant			NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.538+3651T>G		intron_variant		1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.538+3651T>G		intron_variant		1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.538+3651T>G		intron_variant		5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.538+3651T>G		intron_variant				ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7908 AN: 152130 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.0507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0519 AC: 7908 AN: 152248 Hom.: 264 Cov.: 32 AF XY: 0.0541 AC XY: 4024 AN XY: 74432

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.0625

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0533

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0704

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0676 Hom.: 211

Bravo AF: 0.0457

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.87

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: rs17364665; hg19: chr15-48884829;