rs16961207

chr15-48590961-C-Achr15-48590961-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000138.5(FBN1):c.538+5322G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 152,220 control chromosomes in the GnomAD database, including 468 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 0.074 (468 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.565

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.538+5322G>T		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.538+5322G>T		intron_variant
FBN1	NM_001406717.1	c.538+5322G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.538+5322G>T		intron_variant		1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.538+5322G>T		intron_variant, NMD_transcript_variant		1
FBN1	ENST00000537463.6	c.538+5322G>T		intron_variant, NMD_transcript_variant		5
FBN1	ENST00000674301.2	c.538+5322G>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11271 AN: 152102 Hom.: 468 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0713

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0896

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0523

Gnomad OTH AF: 0.0732

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

GnomAD4 genome AF: 0.0740 AC: 11271 AN: 152220 Hom.: 468 Cov.: 32 AF XY: 0.0752 AC XY: 5594 AN XY: 74422

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0712

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.0880

Gnomad4 FIN AF: 0.0713

Gnomad4 NFE AF: 0.0523

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0483 Hom.: 68

Bravo AF: 0.0751

Asia WGS AF: 0.164 AC: 570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	11
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: rs16961207; hg19: chr15-48883158;