NM_032447.5:c.3247C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032447.5(FBN3):c.3247C>T(p.Arg1083Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,609,962 control chromosomes in the GnomAD database, including 3,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1083Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 375 hom., cov: 32)

Exomes 𝑓: 0.048 ( 2936 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.94

Publications

18 publications found

Variant links:

Genes affected

FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

FBN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031781197).

BP6

Variant 19-8118987-G-A is Benign according to our data. Variant chr19-8118987-G-A is described in ClinVar as Benign. ClinVar VariationId is 1540834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.3247C>T	p.Arg1083Trp	missense_variant	Exon 26 of 64	ENST00000600128.6	NP_115823.3	Q75N90A8KAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN3	ENST00000600128.6 link	c.3247C>T	p.Arg1083Trp	missense_variant	Exon 26 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.3247C>T	p.Arg1083Trp	missense_variant	Exon 25 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.3247C>T	p.Arg1083Trp	missense_variant	Exon 26 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.3373C>T	p.Arg1125Trp	missense_variant	Exon 26 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7519

AN:

152160

Hom.:

371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0416

Gnomad FIN

AF:

0.0816

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.0667

GnomAD2 exomes

AF:

0.0713

AC:

17874

AN:

250778

AF XY:

0.0667

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.0786

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0687

GnomAD4 exome

AF:

0.0483

AC:

70358

AN:

1457684

Hom.:

2936

Cov.:

AF XY:

0.0479

AC XY:

34675

AN XY:

724258

show subpopulations

African (AFR)

AF:

0.0114

AC:

381

AN:

33424

American (AMR)

AF:

0.190

AC:

8498

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.0269

AC:

702

AN:

26108

East Asian (EAS)

AF:

0.206

AC:

8144

AN:

39598

South Asian (SAS)

AF:

0.0481

AC:

4140

AN:

86118

European-Finnish (FIN)

AF:

0.0738

AC:

3926

AN:

53186

Middle Eastern (MID)

AF:

0.0528

AC:

304

AN:

5760

European-Non Finnish (NFE)

AF:

0.0371

AC:

41127

AN:

1108738

Other (OTH)

AF:

0.0521

AC:

3136

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3236

6472

9708

12944

16180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1730

3460

5190

6920

8650

<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:

0.0494

AC:

7528

AN:

152278

Hom.:

375

Cov.:

AF XY:

0.0530

AC XY:

3944

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0140

AC:

584

AN:

41582

American (AMR)

AF:

0.141

AC:

2160

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

949

AN:

5174

South Asian (SAS)

AF:

0.0412

AC:

199

AN:

4830

European-Finnish (FIN)

AF:

0.0816

AC:

866

AN:

10618

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0367

AC:

2496

AN:

68018

Other (OTH)

AF:

0.0655

AC:

138

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

343

686

1029

1372

1715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0430

Hom.:

759

Bravo

AF:

0.0549

TwinsUK

AF:

0.0396

AC:

147

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0387

AC:

333

ExAC

AF:

0.0632

AC:

7670

Asia WGS

AF:

0.101

AC:

350

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

FBN3-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D;D

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;.;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;M;M

PhyloP100

1.9

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-6.9

.;D;.

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.039

B;B;B

Vest4

0.38

MPC

0.68

ClinPred

0.086

GERP RS

0.39

Varity_R

0.80

gMVP

0.73

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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