15-48428329-G-C

Position:

• chr15-48428329-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.539

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6997+17C>G		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6997+17C>G		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6997+17C>G		intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103792 AN: 151924 Hom.: 36741 Cov.: 31

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

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.: 47 AF XY: 0.764 AC XY: 555546 AN XY: 726914

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.: 31 AF XY: 0.685 AC XY: 50892 AN XY: 74330

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

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Marfan syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Other links and lift over

dbSNP: rs363832; hg19: chr15-48720526; COSMIC: COSV57330839; COSMIC: COSV57330839;