rs755251

Positions:

• chr15-48519823-A-G
• chr15-48519823-A-T

Variant summary

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

The NM_000138.5(FBN1):​c.1147+836T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,130 control chromosomes in the GnomAD database, including 10,598 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 0.34 (10598 hom., cov: 33)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405

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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1147+836T>C		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1147+836T>C		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1147+836T>C		intron_variant		1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.1147+836T>C		intron_variant		1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.636+17888T>C		intron_variant		5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.1147+836T>C		intron_variant				ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52372 AN: 152012 Hom.: 10570 Cov.: 33

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.345 AC: 52456 AN: 152130 Hom.: 10598 Cov.: 33 AF XY: 0.342 AC XY: 25472 AN XY: 74374

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.319

Alfa AF: 0.246 Hom.: 6309

Bravo AF: 0.358

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.86

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: rs755251; hg19: chr15-48812020;