rs2430347

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006329.4(FBLN5):c.945T>C(p.Ile315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,648 control chromosomes in the GnomAD database, including 449,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44423 hom., cov: 32)

Exomes 𝑓: 0.74 ( 404882 hom. )

Consequence

FBLN5
NM_006329.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.509

Variant links:

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

FBLN5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 14-91881336-A-G is Benign according to our data. Variant chr14-91881336-A-G is described in ClinVar as [Benign]. Clinvar id is 163450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91881336-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.509 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4 linkuse as main transcript	c.945T>C	p.Ile315=	synonymous_variant	9/11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9 linkuse as main transcript	c.945T>C	p.Ile315=	synonymous_variant	9/11	1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes

AF:

0.762

AC:

115905

AN:

152020

Hom.:

44362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.676

Gnomad AMR

AF:

0.829

Gnomad ASJ

AF:

0.640

Gnomad EAS

AF:

0.840

Gnomad SAS

AF:

0.738

Gnomad FIN

AF:

0.737

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.741

Gnomad OTH

AF:

0.751

GnomAD3 exomes

AF:

0.764

AC:

191914

AN:

251290

Hom.:

73853

AF XY:

0.756

AC XY:

102705

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.780

Gnomad AMR exome

AF:

0.876

Gnomad ASJ exome

AF:

0.637

Gnomad EAS exome

AF:

0.835

Gnomad SAS exome

AF:

0.740

Gnomad FIN exome

AF:

0.749

Gnomad NFE exome

AF:

0.737

Gnomad OTH exome

AF:

0.754

GnomAD4 exome

AF:

0.743

AC:

1085841

AN:

1461510

Hom.:

404882

Cov.:

AF XY:

0.742

AC XY:

539652

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.782

Gnomad4 AMR exome

AF:

0.868

Gnomad4 ASJ exome

AF:

0.641

Gnomad4 EAS exome

AF:

0.864

Gnomad4 SAS exome

AF:

0.737

Gnomad4 FIN exome

AF:

0.754

Gnomad4 NFE exome

AF:

0.735

Gnomad4 OTH exome

AF:

0.742

GnomAD4 genome

AF:

0.763

AC:

116030

AN:

152138

Hom.:

44423

Cov.:

AF XY:

0.763

AC XY:

56737

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.787

Gnomad4 AMR

AF:

0.830

Gnomad4 ASJ

AF:

0.640

Gnomad4 EAS

AF:

0.840

Gnomad4 SAS

AF:

0.739

Gnomad4 FIN

AF:

0.737

Gnomad4 NFE

AF:

0.741

Gnomad4 OTH

AF:

0.754

Alfa

AF:

0.742

Hom.:

60375

Bravo

AF:

0.771

Asia WGS

AF:

0.807

AC:

2806

AN:

3478

EpiCase

AF:

0.728

EpiControl

AF:

0.727

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile315Ile in exon 9 of FBLN5: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 25.9% (2226/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2430347). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Macular degeneration, age-related, 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cutis laxa, autosomal dominant 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Cutis laxa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cutis laxa, autosomal recessive, type 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.34

DANN

Benign

0.60

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