rs7175546

Positions:

• chr15-48432499-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.6739+367A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 152,302 control chromosomes in the GnomAD database, including 317 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 0.060 (317 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6739+367A>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6739+367A>G		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6739+367A>G		intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9138 AN: 152182 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.0656

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

GnomAD4 genome AF: 0.0600 AC: 9144 AN: 152302 Hom.: 317 Cov.: 32 AF XY: 0.0611 AC XY: 4553 AN XY: 74486

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0648

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.0953

Gnomad4 FIN AF: 0.0740

Gnomad4 NFE AF: 0.0520

Gnomad4 OTH AF: 0.0715

Alfa AF: 0.0544 Hom.: 53

Bravo AF: 0.0592

Asia WGS AF: 0.169 AC: 588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.50

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: rs7175546; hg19: chr15-48724696;