15-48487034-GTAAAA-G

Variant names:

• chr15-48487034-GTAAAA-G
• rs72158035
• NM_000138.5:c.3589+36_3589+40delTTTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.3589+36_3589+40delTTTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,279,136 control chromosomes in the GnomAD database, including 17,597 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2094 hom., cov: 29)
  • Exomes 𝑓: 0.15 (15503 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00
• Publications: 3 publications found

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]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-48487034-GTAAAA-G is Benign according to our data. Variant chr15-48487034-GTAAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.3589+36_3589+40delTTTTA		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.3589+36_3589+40delTTTTA		intron	N/A	NP_001393645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.3589+36_3589+40delTTTTA		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.3589+36_3589+40delTTTTA		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.637-12389_637-12385delTTTTA		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24574 AN: 150246 Hom.: 2086 Cov.: 29

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.175 AC: 14975 AN: 85474 AF XY: 0.169

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0567

Gnomad EAS exome AF: 0.371

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.153 AC: 172360 AN: 1128774 Hom.: 15503 AF XY: 0.153 AC XY: 85461 AN XY: 558522

African (AFR) AF: 0.177 AC: 3991 AN: 22590

American (AMR) AF: 0.206 AC: 3695 AN: 17900

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1250 AN: 19736

East Asian (EAS) AF: 0.413 AC: 13233 AN: 32036

South Asian (SAS) AF: 0.144 AC: 6991 AN: 48676

European-Finnish (FIN) AF: 0.215 AC: 8573 AN: 39854

Middle Eastern (MID) AF: 0.0864 AC: 284 AN: 3288

European-Non Finnish (NFE) AF: 0.142 AC: 127114 AN: 898018

Other (OTH) AF: 0.155 AC: 7229 AN: 46676

GnomAD4 genome AF: 0.164 AC: 24615 AN: 150362 Hom.: 2094 Cov.: 29 AF XY: 0.167 AC XY: 12295 AN XY: 73410

African (AFR) AF: 0.168 AC: 6858 AN: 40848

American (AMR) AF: 0.175 AC: 2653 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3466

East Asian (EAS) AF: 0.349 AC: 1769 AN: 5062

South Asian (SAS) AF: 0.152 AC: 718 AN: 4736

European-Finnish (FIN) AF: 0.199 AC: 2042 AN: 10252

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9787 AN: 67602

Other (OTH) AF: 0.155 AC: 322 AN: 2076

Alfa AF: 0.0651 Hom.: 107

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs72158035; hg19: chr15-48779231;