rs7246376

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.986C>T(p.Pro329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,612,480 control chromosomes in the GnomAD database, including 40,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4531 hom., cov: 33)

Exomes 𝑓: 0.21 ( 36323 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0290

Publications

23 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=5.2250016E-5).

BP6

Variant 19-8138444-G-A is Benign according to our data. Variant chr19-8138444-G-A is described in ClinVar as Benign. ClinVar VariationId is 1600608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.986C>T	p.Pro329Leu	missense_variant	Exon 9 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FBN3	ENST00000600128.6 link	c.986C>T	p.Pro329Leu	missense_variant	Exon 9 of 64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6 link	c.986C>T	p.Pro329Leu	missense_variant	Exon 8 of 63	1		ENSP00000270509.2
FBN3	ENST00000601739.5 link	c.986C>T	p.Pro329Leu	missense_variant	Exon 9 of 64	1		ENSP00000472324.1
FBN3	ENST00000651877.1 link	c.1112C>T	p.Pro371Leu	missense_variant	Exon 9 of 64			ENSP00000498507.1

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34856

AN:

152090

Hom.:

4517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.472

Gnomad SAS

AF:

0.412

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.287

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.266

AC:

65459

AN:

246014

AF XY:

0.265

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.470

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.207

AC:

302638

AN:

1460272

Hom.:

36323

Cov.:

AF XY:

0.212

AC XY:

154353

AN XY:

726414

show subpopulations

African (AFR)

AF:

0.257

AC:

8604

AN:

33476

American (AMR)

AF:

0.348

AC:

15536

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7620

AN:

26108

East Asian (EAS)

AF:

0.444

AC:

17609

AN:

39682

South Asian (SAS)

AF:

0.405

AC:

34918

AN:

86194

European-Finnish (FIN)

AF:

0.161

AC:

8471

AN:

52578

Middle Eastern (MID)

AF:

0.285

AC:

1639

AN:

5752

European-Non Finnish (NFE)

AF:

0.175

AC:

194714

AN:

1111496

Other (OTH)

AF:

0.224

AC:

13527

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

13125

26249

39374

52498

65623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7326

14652

21978

29304

36630

<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:

0.229

AC:

34905

AN:

152208

Hom.:

4531

Cov.:

AF XY:

0.235

AC XY:

17509

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.255

AC:

10582

AN:

41538

American (AMR)

AF:

0.274

AC:

4198

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

994

AN:

3468

East Asian (EAS)

AF:

0.472

AC:

2437

AN:

5160

South Asian (SAS)

AF:

0.410

AC:

1982

AN:

4830

European-Finnish (FIN)

AF:

0.153

AC:

1619

AN:

10608

Middle Eastern (MID)

AF:

0.295

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12210

AN:

67998

Other (OTH)

AF:

0.234

AC:

494

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1365

2729

4094

5458

6823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.207

Hom.:

10652

Bravo

AF:

0.240

TwinsUK

AF:

0.173

AC:

642

ALSPAC

AF:

0.180

AC:

692

ESP6500AA

AF:

0.254

AC:

1120

ESP6500EA

AF:

0.184

AC:

1579

ExAC

AF:

0.260

AC:

31605

Asia WGS

AF:

0.454

AC:

1576

AN:

3478

EpiCase

AF:

0.191

EpiControl

AF:

0.191

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FBN3-related disorder

Benign:1

Oct 17, 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

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.64

.;.;T

MetaRNN

Benign

0.000052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L

PhyloP100

-0.029

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.29

.;T;.

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.031

B;B;B

Vest4

0.063

MPC

0.20

ClinPred

0.0034

GERP RS

2.0

Varity_R

0.028

gMVP

0.46

Mutation Taster

=99/1

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