15-48428329-G-C

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.6997+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,613,274 control chromosomes in the GnomAD database, including 463,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36747 hom., cov: 31)

Exomes 𝑓: 0.76 ( 426632 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.539

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

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 15-48428329-G-C is Benign according to our data. Variant chr15-48428329-G-C is described in ClinVar as [Benign]. Clinvar id is 137312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48428329-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.6997+17C>G		intron_variant	Intron 57 of 65	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.6997+17C>G		intron_variant	Intron 56 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.6997+17C>G		intron_variant	Intron 57 of 65	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.683

AC:

103792

AN:

151924

Hom.:

36741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.481

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.734

Gnomad ASJ

AF:

0.815

Gnomad EAS

AF:

0.643

Gnomad SAS

AF:

0.803

Gnomad FIN

AF:

0.752

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.771

Gnomad OTH

AF:

0.702

GnomAD3 exomes

AF:

0.746

AC:

186984

AN:

250584

Hom.:

70711

AF XY:

0.754

AC XY:

102171

AN XY:

135472

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.791

Gnomad ASJ exome

AF:

0.806

Gnomad EAS exome

AF:

0.640

Gnomad SAS exome

AF:

0.809

Gnomad FIN exome

AF:

0.744

Gnomad NFE exome

AF:

0.767

Gnomad OTH exome

AF:

0.760

GnomAD4 exome

AF:

0.762

AC:

1113337

AN:

1461232

Hom.:

426632

Cov.:

AF XY:

0.764

AC XY:

555546

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.464

Gnomad4 AMR exome

AF:

0.784

Gnomad4 ASJ exome

AF:

0.805

Gnomad4 EAS exome

AF:

0.658

Gnomad4 SAS exome

AF:

0.812

Gnomad4 FIN exome

AF:

0.742

Gnomad4 NFE exome

AF:

0.771

Gnomad4 OTH exome

AF:

0.750

GnomAD4 genome

AF:

0.683

AC:

103834

AN:

152042

Hom.:

36747

Cov.:

AF XY:

0.685

AC XY:

50892

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.481

Gnomad4 AMR

AF:

0.734

Gnomad4 ASJ

AF:

0.815

Gnomad4 EAS

AF:

0.642

Gnomad4 SAS

AF:

0.803

Gnomad4 FIN

AF:

0.752

Gnomad4 NFE

AF:

0.770

Gnomad4 OTH

AF:

0.702

Alfa

AF:

0.735

Hom.:

7434

Bravo

AF:

0.672

Asia WGS

AF:

0.714

AC:

2485

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 14, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.6997+17C>G alters a non-conserved nucleotide located 17 nucleotides away from a canonical splice site. The variant allele was found at a frequency of 0.74 in 276312 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 6567 fold above the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. The c.6997+17C>G variant has been reported in the literature and these reports classify the variant as a benign polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Marfan syndrome

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.4

DANN

Benign

0.36

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