Genetic Variant NM_006486.3:c.963C>T (chr22-45541269-C-T) – 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_006486.3(FBLN1):c.963C>T(p.Ile321Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,613,910 control chromosomes in the GnomAD database, including 126,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10329 hom., cov: 34)

Exomes 𝑓: 0.39 ( 115750 hom. )

Consequence

FBLN1
NM_006486.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.24

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 22-45541269-C-T is Benign according to our data. Variant chr22-45541269-C-T is described in ClinVar as Benign. ClinVar VariationId is 1232901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBLN1	NM_006486.3	MANE Select	c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 17	NP_006477.3
FBLN1	NM_001996.4		c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 15	NP_001987.3
FBLN1	NM_006485.4		c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 15	NP_006476.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 17	ENSP00000331544.6
FBLN1	ENST00000262722.11	TSL:1	c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 15	ENSP00000262722.7
FBLN1	ENST00000442170.6	TSL:1	c.963C>T	p.Ile321Ile	synonymous	Exon 9 of 15	ENSP00000393812.2

Frequencies

GnomAD3 genomes

AF:

0.356

AC:

54085

AN:

152040

Hom.:

10333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.242

Gnomad AMI

AF:

0.655

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.287

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.360

GnomAD2 exomes

AF:

0.358

AC:

90055

AN:

251468

AF XY:

0.366

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.243

Gnomad ASJ exome

AF:

0.419

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.486

Gnomad NFE exome

AF:

0.425

Gnomad OTH exome

AF:

0.385

GnomAD4 exome

AF:

0.392

AC:

573066

AN:

1461750

Hom.:

115750

Cov.:

AF XY:

0.392

AC XY:

285268

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.233

AC:

7797

AN:

33474

American (AMR)

AF:

0.256

AC:

11438

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

10828

AN:

26134

East Asian (EAS)

AF:

0.178

AC:

7062

AN:

39696

South Asian (SAS)

AF:

0.305

AC:

26284

AN:

86250

European-Finnish (FIN)

AF:

0.478

AC:

25521

AN:

53416

Middle Eastern (MID)

AF:

0.470

AC:

2707

AN:

5760

European-Non Finnish (NFE)

AF:

0.412

AC:

458209

AN:

1111902

Other (OTH)

AF:

0.384

AC:

23220

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

20969

41938

62907

83876

104845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13758

27516

41274

55032

68790

<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:

0.355

AC:

54076

AN:

152160

Hom.:

10329

Cov.:

AF XY:

0.357

AC XY:

26555

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.241

AC:

10026

AN:

41536

American (AMR)

AF:

0.331

AC:

5061

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1432

AN:

3472

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5178

South Asian (SAS)

AF:

0.286

AC:

1381

AN:

4822

European-Finnish (FIN)

AF:

0.490

AC:

5187

AN:

10588

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28580

AN:

67956

Other (OTH)

AF:

0.355

AC:

748

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1741

3481

5222

6962

8703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<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:

0.390

Hom.:

49523

Bravo

AF:

0.338

Asia WGS

AF:

0.203

AC:

706

AN:

3478

EpiCase

AF:

0.426

EpiControl

AF:

0.425

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Synpolydactyly type 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.21

(source)

DANN

Benign

0.64

PhyloP100

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over