Genetic Variant NM_032447.5:c.6031+141G>A (chr19-8091324-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_032447.5(FBN3):c.6031+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0152 (AC=17,471) in the gnomAD database across 1,149,846 control chromosomes, including 1,446 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.198. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.059 ( 869 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 577 hom. )

Consequence

FBN3
NM_032447.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0580

Publications

1 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

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.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1979 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.6031+141G>A		intron	N/A	NP_115823.3
	FBN3	NM_001321431.2		c.6031+141G>A		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.6031+141G>A	intron	N/A	ENSP00000470498.1	Q75N90
FBN3	ENST00000270509.6	TSL:1	c.6031+141G>A	intron	N/A	ENSP00000270509.2	Q75N90
FBN3	ENST00000601739.5	TSL:1	c.6031+141G>A	intron	N/A	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9025

AN:

152138

Hom.:

864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0207

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.0464

GnomAD4 exome

AF:

0.00844

AC:

8415

AN:

997590

Hom.:

577

AF XY:

0.00832

AC XY:

4181

AN XY:

502748

show subpopulations

African (AFR)

AF:

0.203

AC:

4715

AN:

23254

American (AMR)

AF:

0.0139

AC:

409

AN:

29352

Ashkenazi Jewish (ASJ)

AF:

0.0000561

AC:

AN:

17828

East Asian (EAS)

AF:

0.0184

AC:

683

AN:

37196

South Asian (SAS)

AF:

0.0228

AC:

1424

AN:

62428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41994

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

4590

European-Non Finnish (NFE)

AF:

0.000563

AC:

415

AN:

736644

Other (OTH)

AF:

0.0162

AC:

719

AN:

44304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

372

745

1117

1490

1862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0595

AC:

9056

AN:

152256

Hom.:

869

Cov.:

AF XY:

0.0582

AC XY:

4335

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.201

AC:

8348

AN:

41490

American (AMR)

AF:

0.0207

AC:

317

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5190

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000823

AC:

AN:

68036

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

384

768

1152

1536

1920

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

TOPMed (Bravo)

AF:

0.0674

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0529

AC:

1440

AN:

27230

Hom.:

149

Local populations

ABraOM SABE-WGS-1171

AF:

0.0500

AC:

117

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.0249

GenomeAsia100K

AF:

0.0350

AC:

123

AN:

3478

show subpopulations

Oceania

AF:

0.0473

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.0157

AC:

AN:

702

Hom.:

South-East Asia

AF:

0.0448

AC:

AN:

692

Hom.:

South Asia

AF:

0.0200

AC:

AN:

1448

Hom.:

Africa

AF:

0.212

AC:

AN:

208

Hom.:

America

AF:

0.00

AC:

AN:

Hom.:

West Eurasia

AF:

0.00439

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.00885

AC:

AN:

7234

Qatari Genome

AF:

0.0341

AC:

AN:

176

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0180

AC:

2214

AN:

122690

Hom.:

Turkish Variome

AF:

0.00130

AC:

AN:

1544

Hom.:

UK10K

AF:

0.000529

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.00112

AC:

AN:

3574

ALSPAC

AF:

0.00

AC:

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0269

AC:

241

AN:

8960

Hom.:

Case/control cohorts

Cohort

Cases

Controls

SCHEMA

(Schizophrenia)

216 / 65496AF: 0.00329791

280 / 118804AF: 0.00235682

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.1

(source)

DANN

Benign

0.39

PhyloP100

0.058

AlphaGenome AVI

Benign

2.1

(source)

GPN-Star LLR

0.46

(source)

GPN-Star score

-0.46

(source)

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

Pangolin (max)

Benign

0.0

(source)

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over