19-8123928-C-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.2812G>A(p.Val938Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,614,010 control chromosomes in the GnomAD database, including 3,315 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V938V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 398 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2917 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.233

Publications

12 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=0.0022578835).

BP6

Variant 19-8123928-C-T is Benign according to our data. Variant chr19-8123928-C-T is described in ClinVar as Benign. ClinVar VariationId is 1631056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.2812G>A	p.Val938Ile	missense_variant	Exon 23 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.2812G>A	p.Val938Ile	missense_variant	Exon 23 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.2812G>A	p.Val938Ile	missense_variant	Exon 22 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.2812G>A	p.Val938Ile	missense_variant	Exon 23 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.2938G>A	p.Val980Ile	missense_variant	Exon 23 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7513

AN:

152152

Hom.:

395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.0419

Gnomad FIN

AF:

0.0816

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0659

GnomAD2 exomes

AF:

0.0722

AC:

18121

AN:

250900

AF XY:

0.0677

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.0280

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.0781

Gnomad NFE exome

AF:

0.0339

Gnomad OTH exome

AF:

0.0679

GnomAD4 exome

AF:

0.0470

AC:

68766

AN:

1461742

Hom.:

2917

Cov.:

AF XY:

0.0467

AC XY:

33988

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0129

AC:

433

AN:

33480

American (AMR)

AF:

0.190

AC:

8479

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

686

AN:

26136

East Asian (EAS)

AF:

0.213

AC:

8440

AN:

39698

South Asian (SAS)

AF:

0.0483

AC:

4164

AN:

86252

European-Finnish (FIN)

AF:

0.0735

AC:

3918

AN:

53342

Middle Eastern (MID)

AF:

0.0520

AC:

300

AN:

5768

European-Non Finnish (NFE)

AF:

0.0352

AC:

39176

AN:

1111970

Other (OTH)

AF:

0.0525

AC:

3170

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3905

7809

11714

15618

19523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1662

3324

4986

6648

8310

<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:

7519

AN:

152268

Hom.:

398

Cov.:

AF XY:

0.0529

AC XY:

3936

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0152

AC:

634

AN:

41576

American (AMR)

AF:

0.139

AC:

2130

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.199

AC:

1027

AN:

5154

South Asian (SAS)

AF:

0.0413

AC:

199

AN:

4822

European-Finnish (FIN)

AF:

0.0816

AC:

866

AN:

10614

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0352

AC:

2394

AN:

68026

Other (OTH)

AF:

0.0643

AC:

136

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

347

693

1040

1386

1733

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:

0.0450

Hom.:

580

Bravo

AF:

0.0550

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0378

AC:

325

ExAC

AF:

0.0644

AC:

7814

Asia WGS

AF:

0.112

AC:

388

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

0.082

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.74

.;.;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.70

N;N;N

PhyloP100

-0.23

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.50

.;N;.

REVEL

Benign

0.20

Sift

Benign

0.44

.;T;.

Sift4G

Benign

0.64

T;T;T

Polyphen

0.65

P;P;P

Vest4

0.12

MPC

0.16

ClinPred

0.013

GERP RS

-0.095

Varity_R

0.049

gMVP

0.33

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