Genetic Variant FBN3:c.7337-111A>G (chr19-8081230-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032447.5(FBN3):c.7337-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,475,976 control chromosomes in the GnomAD database, including 228,925 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 30194 hom., cov: 31)

Exomes 𝑓: 0.54 ( 198731 hom. )

Consequence

FBN3
NM_032447.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.396

Publications

6 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:

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new If you want to explore the variant's impact on the transcript NM_032447.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.7337-111A>G		intron	N/A	NP_115823.3
	FBN3	NM_001321431.2		c.7337-111A>G		intron	N/A	NP_001308360.1	Q75N90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FBN3	ENST00000600128.6	TSL:1 MANE Select	c.7337-111A>G	intron	N/A	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6	TSL:1	c.7337-111A>G	intron	N/A	ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5	TSL:1	c.7337-111A>G	intron	N/A	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes

AF:

0.616

AC:

93514

AN:

151782

Hom.:

30153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.802

Gnomad AMI

AF:

0.550

Gnomad AMR

AF:

0.611

Gnomad ASJ

AF:

0.407

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.593

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.556

Gnomad OTH

AF:

0.594

GnomAD4 exome

AF:

0.542

AC:

718074

AN:

1324076

Hom.:

198731

Cov.:

AF XY:

0.537

AC XY:

353295

AN XY:

658490

show subpopulations

African (AFR)

AF:

0.809

AC:

24777

AN:

30640

American (AMR)

AF:

0.591

AC:

23096

AN:

39082

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

9178

AN:

22564

East Asian (EAS)

AF:

0.388

AC:

15037

AN:

38742

South Asian (SAS)

AF:

0.384

AC:

29677

AN:

77302

European-Finnish (FIN)

AF:

0.592

AC:

29729

AN:

50176

Middle Eastern (MID)

AF:

0.426

AC:

1994

AN:

4684

European-Non Finnish (NFE)

AF:

0.552

AC:

555477

AN:

1005806

Other (OTH)

AF:

0.528

AC:

29109

AN:

55080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

15806

31612

47419

63225

79031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15386

30772

46158

61544

76930

<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:

0.616

AC:

93616

AN:

151900

Hom.:

30194

Cov.:

AF XY:

0.613

AC XY:

45500

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.802

AC:

33256

AN:

41448

American (AMR)

AF:

0.611

AC:

9332

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

1409

AN:

3464

East Asian (EAS)

AF:

0.368

AC:

1888

AN:

5134

South Asian (SAS)

AF:

0.385

AC:

1849

AN:

4800

European-Finnish (FIN)

AF:

0.593

AC:

6269

AN:

10574

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.556

AC:

37730

AN:

67894

Other (OTH)

AF:

0.594

AC:

1254

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1721

3443

5164

6886

8607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.602

Hom.:

3515

Bravo

AF:

0.625

Asia WGS

AF:

0.438

AC:

1524

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.9

(source)

DANN

Benign

0.62

PhyloP100

0.40

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over