Genetic Variant NM_032447.5:c.6603T>C (chr19-8087841-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032447.5(FBN3):c.6603T>C(p.Asp2201Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,476 control chromosomes in the GnomAD database, including 411,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43759 hom., cov: 31)

Exomes 𝑓: 0.71 ( 367647 hom. )

Consequence

FBN3
NM_032447.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.492

Publications

16 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 19-8087841-A-G is Benign according to our data. Variant chr19-8087841-A-G is described in ClinVar as Benign. ClinVar VariationId is 1603105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.492 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5 link	c.6603T>C	p.Asp2201Asp	synonymous_variant	Exon 53 of 64	ENST00000600128.6	NP_115823.3	Q75N90A8KAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6 link	c.6603T>C	p.Asp2201Asp	synonymous_variant	Exon 53 of 64	1	NM_032447.5	ENSP00000470498.1		Q75N90

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

114034

AN:

151884

Hom.:

43698

Cov.:

show subpopulations

Gnomad AFR

AF:

0.902

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.708

Gnomad ASJ

AF:

0.733

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.722

Gnomad OTH

AF:

0.765

GnomAD2 exomes

AF:

0.681

AC:

171020

AN:

251266

AF XY:

0.677

show subpopulations

Gnomad AFR exome

AF:

0.906

Gnomad AMR exome

AF:

0.644

Gnomad ASJ exome

AF:

0.724

Gnomad EAS exome

AF:

0.509

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.719

Gnomad OTH exome

AF:

0.696

GnomAD4 exome

AF:

0.706

AC:

1031566

AN:

1461474

Hom.:

367647

Cov.:

AF XY:

0.702

AC XY:

510257

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.908

AC:

30386

AN:

33476

American (AMR)

AF:

0.655

AC:

29290

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.728

AC:

19020

AN:

26134

East Asian (EAS)

AF:

0.493

AC:

19589

AN:

39696

South Asian (SAS)

AF:

0.569

AC:

49047

AN:

86256

European-Finnish (FIN)

AF:

0.654

AC:

34905

AN:

53386

Middle Eastern (MID)

AF:

0.718

AC:

4135

AN:

5758

European-Non Finnish (NFE)

AF:

0.722

AC:

802233

AN:

1111664

Other (OTH)

AF:

0.711

AC:

42961

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15300

30601

45901

61202

76502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19852

39704

59556

79408

99260

<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:

0.751

AC:

114143

AN:

152002

Hom.:

43759

Cov.:

AF XY:

0.741

AC XY:

55050

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.902

AC:

37451

AN:

41512

American (AMR)

AF:

0.709

AC:

10821

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.733

AC:

2545

AN:

3470

East Asian (EAS)

AF:

0.494

AC:

2539

AN:

5138

South Asian (SAS)

AF:

0.522

AC:

2516

AN:

4816

European-Finnish (FIN)

AF:

0.646

AC:

6809

AN:

10540

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.722

AC:

49081

AN:

67938

Other (OTH)

AF:

0.758

AC:

1603

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1358

2717

4075

5434

6792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.750

Hom.:

19127

Bravo

AF:

0.769

Asia WGS

AF:

0.530

AC:

1844

AN:

3478

EpiCase

AF:

0.726

EpiControl

AF:

0.728

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.089

(source)

DANN

Benign

0.54

PhyloP100

0.49

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over