NM_032447.5:c.5873C>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.5873C>A(p.Pro1958His) variant causes a missense change. The variant allele was found at a frequency of 0.422 in 1,612,292 control chromosomes in the GnomAD database, including 149,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12817 hom., cov: 34)

Exomes 𝑓: 0.43 ( 137098 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.29

Publications

24 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=2.5079229E-5).

BP6

Variant 19-8094478-G-T is Benign according to our data. Variant chr19-8094478-G-T is described in ClinVar as Benign. ClinVar VariationId is 1297917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.5873C>A	p.Pro1958His	missense_variant	Exon 47 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.5873C>A	p.Pro1958His	missense_variant	Exon 47 of 64	1	NM_032447.5	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6 link	c.5873C>A	p.Pro1958His	missense_variant	Exon 46 of 63	1		ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5 link	c.5873C>A	p.Pro1958His	missense_variant	Exon 47 of 64	1		ENSP00000472324.1	Q75N90
FBN3	ENST00000651877.1 link	c.5999C>A	p.Pro2000His	missense_variant	Exon 47 of 64			ENSP00000498507.1	A0A494C0D8

Frequencies

GnomAD3 genomes

AF:

0.390

AC:

59258

AN:

152012

Hom.:

12801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.472

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.730

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.400

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.468

AC:

116676

AN:

249542

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.606

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.726

Gnomad FIN exome

AF:

0.518

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.440

GnomAD4 exome

AF:

0.425

AC:

621061

AN:

1460162

Hom.:

137098

Cov.:

AF XY:

0.429

AC XY:

311466

AN XY:

726358

show subpopulations

African (AFR)

AF:

0.226

AC:

7552

AN:

33440

American (AMR)

AF:

0.597

AC:

26599

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8963

AN:

26104

East Asian (EAS)

AF:

0.707

AC:

28055

AN:

39654

South Asian (SAS)

AF:

0.560

AC:

48223

AN:

86080

European-Finnish (FIN)

AF:

0.514

AC:

27406

AN:

53332

Middle Eastern (MID)

AF:

0.359

AC:

2070

AN:

5758

European-Non Finnish (NFE)

AF:

0.403

AC:

447228

AN:

1110914

Other (OTH)

AF:

0.414

AC:

24965

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

16418

32836

49253

65671

82089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14136

28272

42408

56544

70680

<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:

0.390

AC:

59296

AN:

152130

Hom.:

12817

Cov.:

AF XY:

0.402

AC XY:

29899

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.233

AC:

9654

AN:

41510

American (AMR)

AF:

0.498

AC:

7607

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1198

AN:

3472

East Asian (EAS)

AF:

0.730

AC:

3776

AN:

5174

South Asian (SAS)

AF:

0.589

AC:

2835

AN:

4816

European-Finnish (FIN)

AF:

0.539

AC:

5702

AN:

10586

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.400

AC:

27207

AN:

67976

Other (OTH)

AF:

0.377

AC:

797

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1767

3533

5300

7066

8833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.395

Hom.:

55926

Bravo

AF:

0.376

TwinsUK

AF:

0.406

AC:

1504

ALSPAC

AF:

0.413

AC:

1592

ESP6500AA

AF:

0.235

AC:

1034

ESP6500EA

AF:

0.387

AC:

3332

ExAC

AF:

0.455

AC:

55211

Asia WGS

AF:

0.600

AC:

2083

AN:

3478

EpiCase

AF:

0.382

EpiControl

AF:

0.381

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Oct 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;T;T

Eigen

Benign

0.021

Eigen_PC

Benign

-0.041

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

.;.;T

MetaRNN

Benign

0.000025

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

M;M;M

PhyloP100

5.3

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.8

.;D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.010

.;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.96

D;D;D

Vest4

0.36

MPC

0.77

ClinPred

0.060

GERP RS

1.4

Varity_R

0.60

gMVP

0.71

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