NM_000138.5:c.6037+54T>A

Variant names:

• chr15-48444487-A-T
• rs2303502
• NM_000138.5:c.6037+54T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.6037+54T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,604,964 control chromosomes in the GnomAD database, including 434,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34483 hom., cov: 32)
  • Exomes 𝑓: 0.74 (400211 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0670
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-48444487-A-T is Benign according to our data. Variant chr15-48444487-A-T is described in ClinVar as Benign. ClinVar VariationId is 1273419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6037+54T>A		intron_variant	Intron 49 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6037+54T>A		intron_variant	Intron 48 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6037+54T>A		intron_variant	Intron 49 of 65	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100588 AN: 151924 Hom.: 34487 Cov.: 32

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.686

GnomAD4 exome AF: 0.739 AC: 1074261 AN: 1452922 Hom.: 400211 AF XY: 0.742 AC XY: 536332 AN XY: 723256

African (AFR) AF: 0.449 AC: 14925 AN: 33254

American (AMR) AF: 0.733 AC: 32656 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 20504 AN: 25990

East Asian (EAS) AF: 0.576 AC: 22824 AN: 39592

South Asian (SAS) AF: 0.776 AC: 66786 AN: 86046

European-Finnish (FIN) AF: 0.726 AC: 38323 AN: 52764

Middle Eastern (MID) AF: 0.714 AC: 4094 AN: 5736

European-Non Finnish (NFE) AF: 0.752 AC: 830691 AN: 1104914

Other (OTH) AF: 0.724 AC: 43458 AN: 60048

GnomAD4 genome AF: 0.662 AC: 100608 AN: 152042 Hom.: 34483 Cov.: 32 AF XY: 0.663 AC XY: 49272 AN XY: 74326

African (AFR) AF: 0.466 AC: 19339 AN: 41464

American (AMR) AF: 0.702 AC: 10718 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2778 AN: 3468

East Asian (EAS) AF: 0.596 AC: 3067 AN: 5144

South Asian (SAS) AF: 0.754 AC: 3638 AN: 4824

European-Finnish (FIN) AF: 0.735 AC: 7777 AN: 10582

Middle Eastern (MID) AF: 0.771 AC: 225 AN: 292

European-Non Finnish (NFE) AF: 0.752 AC: 51106 AN: 67976

Other (OTH) AF: 0.687 AC: 1447 AN: 2106

Alfa AF: 0.699 Hom.: 4735

Bravo AF: 0.649

Asia WGS AF: 0.654 AC: 2274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.62
DANN	Benign	0.51
PhyloP100		-0.067
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: rs2303502; hg19: chr15-48736684; COSMIC: COSV57309625;