chr19-8095450-G-A

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.5710C>T(p.Leu1904Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,136 control chromosomes in the GnomAD database, including 67,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5154 hom., cov: 32)

Exomes 𝑓: 0.28 ( 61935 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.210

Publications

25 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=9.2354417E-4).

BP6

Variant 19-8095450-G-A is Benign according to our data. Variant chr19-8095450-G-A is described in ClinVar as Benign. ClinVar VariationId is 1562448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.5710C>T	p.Leu1904Phe	missense	Exon 46 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.5710C>T	p.Leu1904Phe	missense	Exon 46 of 64	NP_001308360.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBN3	ENST00000600128.6	TSL:1 MANE Select	c.5710C>T	p.Leu1904Phe	missense	Exon 46 of 64	ENSP00000470498.1
FBN3	ENST00000270509.6	TSL:1	c.5710C>T	p.Leu1904Phe	missense	Exon 45 of 63	ENSP00000270509.2
FBN3	ENST00000601739.5	TSL:1	c.5710C>T	p.Leu1904Phe	missense	Exon 46 of 64	ENSP00000472324.1

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36089

AN:

151878

Hom.:

5142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0889

Gnomad AMI

AF:

0.367

Gnomad AMR

AF:

0.278

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.268

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.306

AC:

76956

AN:

251238

AF XY:

0.310

show subpopulations

Gnomad AFR exome

AF:

0.0840

Gnomad AMR exome

AF:

0.351

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.337

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.284

AC:

414952

AN:

1461140

Hom.:

61935

Cov.:

AF XY:

0.288

AC XY:

209193

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.0827

AC:

2766

AN:

33462

American (AMR)

AF:

0.340

AC:

15178

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

6496

AN:

26104

East Asian (EAS)

AF:

0.447

AC:

17732

AN:

39658

South Asian (SAS)

AF:

0.420

AC:

36209

AN:

86216

European-Finnish (FIN)

AF:

0.336

AC:

17952

AN:

53370

Middle Eastern (MID)

AF:

0.244

AC:

1408

AN:

5766

European-Non Finnish (NFE)

AF:

0.270

AC:

300614

AN:

1111532

Other (OTH)

AF:

0.275

AC:

16597

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

13920

27840

41761

55681

69601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10288

20576

30864

41152

51440

<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:

0.238

AC:

36106

AN:

151996

Hom.:

5154

Cov.:

AF XY:

0.247

AC XY:

18372

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0889

AC:

3690

AN:

41496

American (AMR)

AF:

0.278

AC:

4238

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

854

AN:

3460

East Asian (EAS)

AF:

0.467

AC:

2415

AN:

5166

South Asian (SAS)

AF:

0.464

AC:

2232

AN:

4808

European-Finnish (FIN)

AF:

0.344

AC:

3623

AN:

10536

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.268

AC:

18189

AN:

67952

Other (OTH)

AF:

0.225

AC:

476

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1328

2656

3984

5312

6640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.259

Hom.:

26844

Bravo

AF:

0.220

TwinsUK

AF:

0.262

AC:

971

ALSPAC

AF:

0.283

AC:

1090

ESP6500AA

AF:

0.0937

AC:

413

ESP6500EA

AF:

0.253

AC:

2173

ExAC

AF:

0.302

AC:

36644

Asia WGS

AF:

0.428

AC:

1489

AN:

3478

EpiCase

AF:

0.259

EpiControl

AF:

0.259

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.9

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.095

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.37

MetaRNN

Benign

0.00092

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.18

PhyloP100

-0.21

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.49

REVEL

Benign

0.17

Sift

Benign

0.70

Sift4G

Benign

0.79

Polyphen

0.059

Vest4

0.045

MPC

0.23

ClinPred

0.0010

GERP RS

-0.66

Varity_R

0.044

gMVP

0.60

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over