15-48467094-G-T

Variant names:

• chr15-48467094-G-T
• rs4774517
• NM_000138.5:c.4747+844C>A

Variant summary

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

The NM_000138.5(FBN1):​c.4747+844C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 151,986 control chromosomes in the GnomAD database, including 9,660 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 (9660 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303

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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4747+844C>A		intron_variant	Intron 38 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4747+844C>A		intron_variant	Intron 37 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4747+844C>A		intron_variant	Intron 38 of 65	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50854 AN: 151868 Hom.: 9624 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.335 AC: 50958 AN: 151986 Hom.: 9660 Cov.: 32 AF XY: 0.334 AC XY: 24840 AN XY: 74284

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.312

Alfa AF: 0.266 Hom.: 2728

Bravo AF: 0.347

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.45
DANN	Benign	0.48

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: rs4774517; hg19: chr15-48759291;