15-48448739-GA-GAA

Variant names:

• chr15-48448739-G-GA
• rs55649234
• NM_000138.5:c.5671+28dupT

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.5671+28dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,604,668 control chromosomes in the GnomAD database, including 720 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (70 hom., cov: 32)
  • Exomes 𝑓: 0.022 (650 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.379
• Publications: 2 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 15-48448739-G-GA is Benign according to our data. Variant chr15-48448739-G-GA is described in ClinVar as Benign. ClinVar VariationId is 255301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0771 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.5671+28dupT		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.5671+28dupT		intron	N/A	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.5671+28_5671+29insT		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.5671+28_5671+29insT		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.*1434+28_*1434+29insT		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3319 AN: 151960 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0834

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0260

GnomAD2 exomes AF: 0.0282 AC: 6956 AN: 246962 AF XY: 0.0268

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.0526

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0752

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0218 AC: 31623 AN: 1452590 Hom.: 650 Cov.: 30 AF XY: 0.0220 AC XY: 15878 AN XY: 722882

African (AFR) AF: 0.0141 AC: 468 AN: 33262

American (AMR) AF: 0.0520 AC: 2314 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 414 AN: 25982

East Asian (EAS) AF: 0.110 AC: 4313 AN: 39338

South Asian (SAS) AF: 0.0355 AC: 3037 AN: 85634

European-Finnish (FIN) AF: 0.0146 AC: 754 AN: 51752

Middle Eastern (MID) AF: 0.0254 AC: 146 AN: 5738

European-Non Finnish (NFE) AF: 0.0168 AC: 18582 AN: 1106448

Other (OTH) AF: 0.0266 AC: 1595 AN: 59952

GnomAD4 genome AF: 0.0219 AC: 3325 AN: 152078 Hom.: 70 Cov.: 32 AF XY: 0.0231 AC XY: 1720 AN XY: 74316

African (AFR) AF: 0.0153 AC: 633 AN: 41494

American (AMR) AF: 0.0349 AC: 533 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.0836 AC: 433 AN: 5180

South Asian (SAS) AF: 0.0484 AC: 233 AN: 4814

European-Finnish (FIN) AF: 0.0174 AC: 183 AN: 10546

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1115 AN: 67986

Other (OTH) AF: 0.0257 AC: 54 AN: 2102

Alfa AF: 0.0175 Hom.: 2

Bravo AF: 0.0233

Asia WGS AF: 0.0710 AC: 246 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=100/0	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: rs55649234; hg19: chr15-48740936;