chr15-48487034-GTAAAATAAAATAAAA-G

Position:

• chr15-48487034-GTAAAATAAAATAAAA-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000138.5(FBN1):​c.3589+26_3589+40del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,280,746 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.919

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3589+26_3589+40del		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3589+26_3589+40del		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3589+26_3589+40del		intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150370 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000234 AC: 2 AN: 85474 Hom.: 0 AF XY: 0.0000210 AC XY: 1 AN XY: 47730

Gnomad AFR exome AF: 0.000288

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000973 AC: 11 AN: 1130260 Hom.: 0 AF XY: 0.00000537 AC XY: 3 AN XY: 559180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000558

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000890

Gnomad4 OTH exome AF: 0.0000214

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150486 Hom.: 0 Cov.: 29 AF XY: 0.0000136 AC XY: 1 AN XY: 73466

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72158035; hg19: chr15-48779231;