rs6493328

Positions:

• chr15-48527305-G-A

Variant summary

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

The NM_000138.5(FBN1):​c.863-1050C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 152,108 control chromosomes in the GnomAD database, including 22,224 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 0.48 (22224 hom., cov: 33)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02

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]

LOC124903488 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.863-1050C>T		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.863-1050C>T		intron_variant			NP_001393645.1
LOC124903488	XR_007064628.1	n.1055G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.863-1050C>T		intron_variant		1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.863-1050C>T		intron_variant		1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.636+10406C>T		intron_variant		5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.863-1050C>T		intron_variant				ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73258 AN: 151990 Hom.: 22161 Cov.: 33

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.482 AC: 73388 AN: 152108 Hom.: 22224 Cov.: 33 AF XY: 0.479 AC XY: 35648 AN XY: 74350

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.564

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.346

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.441

Alfa AF: 0.343 Hom.: 10373

Bravo AF: 0.502

Asia WGS AF: 0.560 AC: 1946 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.52

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: rs6493328; hg19: chr15-48819502;