15-48487034-G-GTAAAA

Position:

• chr15-48487034-G-GTAAAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000138.5(FBN1):​c.3589+40_3589+41insTTTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,280,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00127 (191/150480) while in subpopulation AFR AF= 0.00362 (148/40890). AF 95% confidence interval is 0.00314. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 191 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3589+40_3589+41insTTTTA		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3589+40_3589+41insTTTTA		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3589+40_3589+41insTTTTA		intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 190 AN: 150364 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00358

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000384

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.000175 AC: 15 AN: 85474 Hom.: 0 AF XY: 0.000189 AC XY: 9 AN XY: 47730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.000175

Gnomad SAS exome AF: 0.000145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.000219 AC: 248 AN: 1130198 Hom.: 0 Cov.: 13 AF XY: 0.000216 AC XY: 121 AN XY: 559152

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000152

Gnomad4 EAS exome AF: 0.000187

Gnomad4 SAS exome AF: 0.000370

Gnomad4 FIN exome AF: 0.000100

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.00127 AC: 191 AN: 150480 Hom.: 0 Cov.: 29 AF XY: 0.00125 AC XY: 92 AN XY: 73464

Gnomad4 AFR AF: 0.00362

Gnomad4 AMR AF: 0.000594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000384

Gnomad4 OTH AF: 0.000481

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

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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;