rs80338765

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_006329.4(FBLN5):c.604G>A(p.Gly202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,605,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

FBLN5
NM_006329.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:1

Conservation

PhyloP100: 2.13

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24265203).

BP6

Variant 14-91891236-C-T is Benign according to our data. Variant chr14-91891236-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21453.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN5	NM_006329.4 link	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 11	ENST00000342058.9	NP_006320.2	Q9UBX5A0A024R6G3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9 link	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 11	1	NM_006329.4	ENSP00000345008.4		Q9UBX5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251462

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000223

AC:

324

AN:

1453188

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

151

AN XY:

723672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jan 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBLN5 c.604G>A; p.Gly202Arg variant (rs80338765) is reported in the literature in an individual affected with acquired cutis laxa who also carried two variants in the ELN gene (Hu 2006), but is also reported in healthy controls (Jones 2010, Lotery 2006). One functional study demonstrates no effects on structure or secretion (Schneider 2010), but other studies show increased binding of the variant protein to tropoelastin (Hu 2006, Jones 2010). This variant is also reported in ClinVar (Variation ID: 21453), and is found in the Latino/Admixed American population with an allele frequency of 0.11% (39/35438 alleles) in the Genome Aggregation Database. The glycine at codon 202 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.856). Based on available information, the clinical significance of the p.Gly202Arg variant is uncertain at this time. References: Hu Q et al. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol. 2006 Feb;126(2):283-90. PMID: 16374472. Jones RP et al. Structural effects of fibulin 5 missense mutations associated with age-related macular degeneration and cutis laxa. Invest Ophthalmol Vis Sci. 2010 May;51(5):2356-62. PMID: 20007835. Lotery AJ et al. Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa. Hum Mutat. 2006 Jun;27(6):568-74. PMID: 16652333. Schneider R et al. Biophysical characterisation of fibulin-5 proteins associated with disease. J Mol Biol. 2010 Aug 27;401(4):605-17. PMID: 20599547. -

Nov 29, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with cutis laxa and in control cohorts (Hu et al., 2006; Lotery et al., 2006); While one functional study suggests that G202R may increase binding to tropoelastin (Jones et al., 2010), another study demonstrated that this variant did not affect the structure or calcium-binding properties of fibulin-5 (Schneider et al., 2010); both authors concluded that this variant is not sufficient to cause disease (Schneider et al., 2010; Jones et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20007835, 16652333, 16374472, 20599547, 17035250) -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the FBLN5 protein (p.Gly202Arg). This variant is present in population databases (rs80338765, gnomAD 0.09%). This missense change has been observed in individual(s) with cutis laxa and aortic aneurysm (PMID: 16374472). ClinVar contains an entry for this variant (Variation ID: 21453). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FBLN5 function (PMID: 16374472, 16652333, 20007835, 20599547). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cutis laxa, autosomal dominant

Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Macular degeneration, age-related, 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cutis laxa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cutis laxa, autosomal recessive, type 1A

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.1

N;N;N

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.21

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.52

MutPred

0.63

Gain of catalytic residue at R244 (P = 0.0179);.;.;

MVP

0.88

MPC

1.2

ClinPred

0.17

GERP RS

5.0

Varity_R

0.28

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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