15-48534224-CAGAG-CAG

Variant names:

• chr15-48534224-CAG-C
• rs72041020
• NM_000138.5:c.737-21_737-20delCT

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.737-21_737-20delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,574,630 control chromosomes in the GnomAD database, including 402 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (209 hom., cov: 32)
  • Exomes 𝑓: 0.011 (193 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.707
• 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):

• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Acromicric dysplasia

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

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

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

ACMG classification

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

• BP6: Variant 15-48534224-CAG-C is Benign according to our data. Variant chr15-48534224-CAG-C is described in ClinVar as Benign. ClinVar VariationId is 255309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 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.737-21_737-20delCT		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.737-21_737-20delCT		intron	N/A	NP_001393645.1	P35555
	FBN1	NM_001406717.1		c.737-21_737-20delCT		intron	N/A	NP_001393646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.737-21_737-20delCT		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.737-21_737-20delCT		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.636+3485_636+3486delCT		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3476 AN: 145364 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.0202

Gnomad FIN AF: 0.00394

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0238

GnomAD2 exomes AF: 0.0296 AC: 6584 AN: 222242 AF XY: 0.0260

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.0686

Gnomad ASJ exome AF: 0.000769

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0108 AC: 15398 AN: 1429160 Hom.: 193 AF XY: 0.0105 AC XY: 7473 AN XY: 710674

African (AFR) AF: 0.0291 AC: 919 AN: 31550

American (AMR) AF: 0.0650 AC: 2569 AN: 39512

Ashkenazi Jewish (ASJ) AF: 0.000875 AC: 22 AN: 25156

East Asian (EAS) AF: 0.225 AC: 8612 AN: 38340

South Asian (SAS) AF: 0.0151 AC: 1222 AN: 81168

European-Finnish (FIN) AF: 0.00315 AC: 157 AN: 49898

Middle Eastern (MID) AF: 0.00410 AC: 23 AN: 5608

European-Non Finnish (NFE) AF: 0.000749 AC: 823 AN: 1099172

Other (OTH) AF: 0.0179 AC: 1051 AN: 58756

GnomAD4 genome AF: 0.0240 AC: 3493 AN: 145470 Hom.: 209 Cov.: 32 AF XY: 0.0261 AC XY: 1844 AN XY: 70522

African (AFR) AF: 0.0333 AC: 1333 AN: 39974

American (AMR) AF: 0.0485 AC: 710 AN: 14638

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3430

East Asian (EAS) AF: 0.241 AC: 1204 AN: 4994

South Asian (SAS) AF: 0.0200 AC: 91 AN: 4544

European-Finnish (FIN) AF: 0.00394 AC: 35 AN: 8890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00106 AC: 70 AN: 65880

Other (OTH) AF: 0.0245 AC: 49 AN: 1998

Alfa AF: 0.00240 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs72041020; hg19: chr15-48826421;