15-48487034-GTAAAATAAAATAAAA-GTAAAATAAAATAAAATAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000138.5(FBN1):​c.3589+36_3589+40dupTTTTA 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
• 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: Likely_benign. The variant received -1 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.3589+40_3589+41insTTTTA		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.3589+40_3589+41insTTTTA		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.637-12385_637-12384insTTTTA		intron	N/A	ENSP00000440294.2

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

GnomAD2 exomes AF: 0.000175 AC: 15 AN: 85474 AF XY: 0.000189

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 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

African (AFR) AF: 0.00270 AC: 61 AN: 22608

American (AMR) AF: 0.000335 AC: 6 AN: 17906

Ashkenazi Jewish (ASJ) AF: 0.000152 AC: 3 AN: 19746

East Asian (EAS) AF: 0.000187 AC: 6 AN: 32060

South Asian (SAS) AF: 0.000370 AC: 18 AN: 48710

European-Finnish (FIN) AF: 0.000100 AC: 4 AN: 39942

Middle Eastern (MID) AF: 0.000304 AC: 1 AN: 3292

European-Non Finnish (NFE) AF: 0.000153 AC: 138 AN: 899208

Other (OTH) AF: 0.000235 AC: 11 AN: 46726

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

African (AFR) AF: 0.00362 AC: 148 AN: 40890

American (AMR) AF: 0.000594 AC: 9 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5066

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000384 AC: 26 AN: 67632

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00 Hom.: 107

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

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;