14-91881336-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006329.4(FBLN5):c.945T>C(p.Ile315Ile) 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:16

Conservation

PhyloP100: -0.509

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

cutis laxa, autosomal dominant 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
cutis laxa, autosomal recessive, type 1A
Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
Charcot-Marie-Tooth disease, demyelinating, IIA 1H
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
demyelinating hereditary motor and sensory neuropathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
macular degeneration, age-related, 3
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
autosomal dominant cutis laxa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary sensorimotor neuropathy with hyperelastic skin
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive cutis laxa type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FBLN5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 163450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FBLN5	NM_006329.4 link	c.945T>C	p.Ile315Ile	synonymous_variant	Exon 9 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.945T>C	p.Ile315Ile	synonymous_variant	Exon 9 of 11	1	NM_006329.4	ENSP00000345008.4		Q9UBX5

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

GnomAD2 exomes

AF:

0.764

AC:

191914

AN:

251290

AF XY:

0.756

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 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

African (AFR)

AF:

0.782

AC:

26187

AN:

33474

American (AMR)

AF:

0.868

AC:

38841

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

16747

AN:

26126

East Asian (EAS)

AF:

0.864

AC:

34288

AN:

39698

South Asian (SAS)

AF:

0.737

AC:

63523

AN:

86248

European-Finnish (FIN)

AF:

0.754

AC:

40258

AN:

53408

Middle Eastern (MID)

AF:

0.711

AC:

4100

AN:

5768

European-Non Finnish (NFE)

AF:

0.735

AC:

817074

AN:

1111680

Other (OTH)

AF:

0.742

AC:

44823

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15560

31120

46680

62240

77800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20146

40292

60438

80584

100730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.763

AC:

116030

AN:

152138

Hom.:

44423

Cov.:

AF XY:

0.763

AC XY:

56737

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.787

AC:

32633

AN:

41480

American (AMR)

AF:

0.830

AC:

12684

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.640

AC:

2222

AN:

3472

East Asian (EAS)

AF:

0.840

AC:

4351

AN:

5180

South Asian (SAS)

AF:

0.739

AC:

3562

AN:

4822

European-Finnish (FIN)

AF:

0.737

AC:

7797

AN:

10584

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.741

AC:

50386

AN:

68000

Other (OTH)

AF:

0.754

AC:

1589

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1415

2830

4246

5661

7076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.746

Hom.:

89567

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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Sep 29, 2016

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration, age-related, 3

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa, autosomal dominant 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cutis laxa, autosomal recessive, type 1A

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

-0.78

CADD

Benign

0.34

(source)

DANN

Benign

0.60

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over