rs33967815

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.4840G>A(p.Gly1614Ser) variant causes a missense change. The variant allele was found at a frequency of 0.287 in 1,612,494 control chromosomes in the GnomAD database, including 72,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4893 hom., cov: 31)

Exomes 𝑓: 0.29 ( 67163 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.59

Publications

21 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=0.0020065904).

BP6

Variant 19-8103661-C-T is Benign according to our data. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8103661-C-T is described in CliVar as Benign. Clinvar id is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.4840G>A	p.Gly1614Ser	missense_variant	Exon 39 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.4840G>A	p.Gly1614Ser	missense_variant	Exon 39 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.4840G>A	p.Gly1614Ser	missense_variant	Exon 38 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.4840G>A	p.Gly1614Ser	missense_variant	Exon 39 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.4966G>A	p.Gly1656Ser	missense_variant	Exon 39 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34488

AN:

151834

Hom.:

4897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0810

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.326

Gnomad OTH

AF:

0.262

GnomAD2 exomes

AF:

0.244

AC:

61177

AN:

251112

AF XY:

0.251

show subpopulations

Gnomad AFR exome

AF:

0.0778

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.0561

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.293

AC:

428578

AN:

1460542

Hom.:

67163

Cov.:

AF XY:

0.292

AC XY:

212467

AN XY:

726626

show subpopulations

African (AFR)

AF:

0.0749

AC:

2505

AN:

33456

American (AMR)

AF:

0.152

AC:

6806

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8826

AN:

26092

East Asian (EAS)

AF:

0.0568

AC:

2254

AN:

39672

South Asian (SAS)

AF:

0.195

AC:

16772

AN:

86222

European-Finnish (FIN)

AF:

0.255

AC:

13603

AN:

53326

Middle Eastern (MID)

AF:

0.328

AC:

1887

AN:

5760

European-Non Finnish (NFE)

AF:

0.323

AC:

358966

AN:

1110970

Other (OTH)

AF:

0.281

AC:

16959

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14147

28294

42442

56589

70736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11130

22260

33390

44520

55650

<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:

0.227

AC:

34478

AN:

151952

Hom.:

4893

Cov.:

AF XY:

0.221

AC XY:

16437

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.0809

AC:

3355

AN:

41454

American (AMR)

AF:

0.202

AC:

3076

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

1226

AN:

3470

East Asian (EAS)

AF:

0.0555

AC:

287

AN:

5172

South Asian (SAS)

AF:

0.179

AC:

865

AN:

4822

European-Finnish (FIN)

AF:

0.246

AC:

2592

AN:

10534

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.326

AC:

22153

AN:

67944

Other (OTH)

AF:

0.262

AC:

551

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1260

2521

3781

5042

6302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.293

Hom.:

24645

Bravo

AF:

0.218

TwinsUK

AF:

0.320

AC:

1185

ALSPAC

AF:

0.318

AC:

1227

ESP6500AA

AF:

0.0856

AC:

377

ESP6500EA

AF:

0.337

AC:

2900

ExAC

AF:

0.247

AC:

29969

Asia WGS

AF:

0.126

AC:

437

AN:

3478

EpiCase

AF:

0.338

EpiControl

AF:

0.336

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 18, 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

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;.;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.68

N;N;N

PhyloP100

5.6

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.4

.;D;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.024

.;D;.

Sift4G

Uncertain

0.049

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.37

MPC

0.65

ClinPred

0.019

GERP RS

3.6

Varity_R

0.49

gMVP

0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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