rs16961125

Positions:

• chr15-48548847-T-C

Variant summary

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

The NM_000138.5(FBN1):​c.539-11039A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 152,326 control chromosomes in the GnomAD database, including 210 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 0.017 (210 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.648

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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.539-11039A>G		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.539-11039A>G		intron_variant
FBN1	NM_001406717.1	c.539-11039A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.539-11039A>G		intron_variant		1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.539-11039A>G		intron_variant, NMD_transcript_variant		1
FBN1	ENST00000537463.6	c.539-11039A>G		intron_variant, NMD_transcript_variant		5
FBN1	ENST00000674301.2	c.539-11039A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2535 AN: 152208 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0447

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0210

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

GnomAD4 genome AF: 0.0167 AC: 2548 AN: 152326 Hom.: 210 Cov.: 32 AF XY: 0.0194 AC XY: 1447 AN XY: 74486

Gnomad4 AFR AF: 0.00849

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0128 Hom.: 13

Bravo AF: 0.0211

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.76

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: rs16961125; hg19: chr15-48841044;