rs363823

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000138.5(FBN1):c.6617-21A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,612,404 control chromosomes in the GnomAD database, including 777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.029 ( 97 hom., cov: 32)

Exomes 𝑓: 0.022 ( 680 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 15-48433009-T-A is Benign according to our data. Variant chr15-48433009-T-A is described in ClinVar as [Benign]. Clinvar id is 255308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48433009-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.6617-21A>T		intron_variant	Intron 54 of 65	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.6617-21A>T		intron_variant	Intron 53 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.6617-21A>T		intron_variant	Intron 54 of 65	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4374

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0399

Gnomad AMI

AF:

0.0980

Gnomad AMR

AF:

0.0383

Gnomad ASJ

AF:

0.0139

Gnomad EAS

AF:

0.0818

Gnomad SAS

AF:

0.0469

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0299

AC:

7479

AN:

250426

Hom.:

207

AF XY:

0.0281

AC XY:

3798

AN XY:

135312

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.0540

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0741

Gnomad SAS exome

AF:

0.0402

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0314

GnomAD4 exome

AF:

0.0223

AC:

32497

AN:

1460260

Hom.:

680

Cov.:

AF XY:

0.0223

AC XY:

16219

AN XY:

726426

show subpopulations

Gnomad4 AFR exome

AF:

0.0396

Gnomad4 AMR exome

AF:

0.0537

Gnomad4 ASJ exome

AF:

0.0159

Gnomad4 EAS exome

AF:

0.107

Gnomad4 SAS exome

AF:

0.0357

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.0166

Gnomad4 OTH exome

AF:

0.0285

GnomAD4 genome

AF:

0.0288

AC:

4386

AN:

152144

Hom.:

Cov.:

AF XY:

0.0298

AC XY:

2220

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0400

Gnomad4 AMR

AF:

0.0385

Gnomad4 ASJ

AF:

0.0139

Gnomad4 EAS

AF:

0.0820

Gnomad4 SAS

AF:

0.0474

Gnomad4 FIN

AF:

0.0172

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0207

Hom.:

Bravo

AF:

0.0315

Asia WGS

AF:

0.0710

AC:

248

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 10, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.2

DANN

Benign

0.58

La Branchor

0.72

BranchPoint Hunter

3.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over