15-48422641-T-G

Variant names:

• chr15-48422641-T-G
• rs1467953
• NM_000138.5:c.7454-573A>C

Variant summary

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

The NM_000138.5(FBN1):​c.7454-573A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,150 control chromosomes in the GnomAD database, including 33,320 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 0.64 (33320 hom., cov: 33)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7454-573A>C		intron_variant	Intron 60 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7454-573A>C		intron_variant	Intron 59 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7454-573A>C		intron_variant	Intron 60 of 65	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.645 AC: 98080 AN: 152032 Hom.: 33328 Cov.: 33

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.671

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

GnomAD4 genome AF: 0.645 AC: 98097 AN: 152150 Hom.: 33320 Cov.: 33 AF XY: 0.646 AC XY: 48033 AN XY: 74382

Gnomad4 AFR AF: 0.413

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.800

Gnomad4 EAS AF: 0.560

Gnomad4 SAS AF: 0.754

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.671

Alfa AF: 0.733 Hom.: 34590

Bravo AF: 0.630

Asia WGS AF: 0.640 AC: 2226 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.36

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: rs1467953; hg19: chr15-48714838;