Genetic Variant NM_006486.3:c.1698-8487G>T (chr22-45566024-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_006486.3(FBLN1):c.1698-8487G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 152,738 control chromosomes in the GnomAD database, including 32,587 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 0.65 ( 32449 hom., cov: 32)

Exomes 𝑓: 0.61 ( 138 hom. )

Consequence

FBLN1
NM_006486.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.944

Publications

11 publications found

Variant links:

Genes affected

FBLN1 (HGNC:3600): (fibulin 1) Fibulin 1 is a secreted glycoprotein that becomes incorporated into a fibrillar extracellular matrix. Calcium-binding is apparently required to mediate its binding to laminin and nidogen. It mediates platelet adhesion via binding fibrinogen. Four splice variants which differ in the 3' end have been identified. Each variant encodes a different isoform, but no functional distinctions have been identified among the four variants. [provided by RefSeq, Jul 2008]

FBLN1 Gene-Disease associations (from GenCC):

FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
synpolydactyly type 2
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

FBLN1 links:

Genome browser will be placed here

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=-1.02).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3 link	c.1698-8487G>T		intron_variant	Intron 14 of 16	ENST00000327858.11	NP_006477.3	P23142-1Q8NBH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11 link	c.1698-8487G>T		intron_variant	Intron 14 of 16	1	NM_006486.3	ENSP00000331544.6		P23142-1

Frequencies

GnomAD3 genomes

AF:

0.653

AC:

99177

AN:

151928

Hom.:

32416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.663

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.653

Gnomad FIN

AF:

0.631

Gnomad MID

AF:

0.725

Gnomad NFE

AF:

0.634

Gnomad OTH

AF:

0.649

GnomAD4 exome

AF:

0.614

AC:

425

AN:

692

Hom.:

138

AF XY:

0.632

AC XY:

264

AN XY:

418

show subpopulations

African (AFR)

AF:

0.571

AC:

AN:

American (AMR)

AF:

0.813

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.700

AC:

AN:

East Asian (EAS)

AF:

0.167

AC:

AN:

South Asian (SAS)

AF:

0.706

AC:

AN:

European-Finnish (FIN)

AF:

0.438

AC:

AN:

Middle Eastern (MID)

AF:

0.480

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.651

AC:

241

AN:

370

Other (OTH)

AF:

0.675

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.653

AC:

99258

AN:

152046

Hom.:

32449

Cov.:

AF XY:

0.652

AC XY:

48487

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.704

AC:

29182

AN:

41474

American (AMR)

AF:

0.618

AC:

9447

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.627

AC:

2173

AN:

3466

East Asian (EAS)

AF:

0.646

AC:

3337

AN:

5164

South Asian (SAS)

AF:

0.653

AC:

3147

AN:

4816

European-Finnish (FIN)

AF:

0.631

AC:

6674

AN:

10584

Middle Eastern (MID)

AF:

0.728

AC:

214

AN:

294

European-Non Finnish (NFE)

AF:

0.634

AC:

43119

AN:

67962

Other (OTH)

AF:

0.649

AC:

1362

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1781

3562

5342

7123

8904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.869

Hom.:

20546

Bravo

AF:

0.657

Asia WGS

AF:

0.611

AC:

2125

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.56

(source)

DANN

Benign

0.20

PhyloP100

-0.94

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

Computational scores

Splicing

Publications

Other links and lift over