Genetic Variant FBLN1:p.Ile321Ile (chr22-45541269-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1232901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-45541269-C-T is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3 link	c.963C>T	p.Ile321Ile	synonymous_variant	Exon 9 of 17	ENST00000327858.11	NP_006477.3	P23142-1Q8NBH6
FBLN1	NM_001996.4 link	c.963C>T	p.Ile321Ile	synonymous_variant	Exon 9 of 15		NP_001987.3	P23142-4A0A8S0LWY1
FBLN1	NM_006485.4 link	c.963C>T	p.Ile321Ile	synonymous_variant	Exon 9 of 15		NP_006476.3	P23142-3Q8NBH6
FBLN1	NM_006487.3 link	c.963C>T	p.Ile321Ile	synonymous_variant	Exon 9 of 15		NP_006478.3	P23142-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11 link	c.963C>T	p.Ile321Ile	synonymous_variant	Exon 9 of 17	1	NM_006486.3	ENSP00000331544.6		P23142-1

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

GnomAD3 exomes

AF:

0.358

AC:

90055

AN:

251468

Hom.:

17578

AF XY:

0.366

AC XY:

49676

AN XY:

135912

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 SAS exome

AF:

0.297

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

Gnomad4 AFR exome

AF:

0.233

Gnomad4 AMR exome

AF:

0.256

Gnomad4 ASJ exome

AF:

0.414

Gnomad4 EAS exome

AF:

0.178

Gnomad4 SAS exome

AF:

0.305

Gnomad4 FIN exome

AF:

0.478

Gnomad4 NFE exome

AF:

0.412

Gnomad4 OTH exome

AF:

0.384

GnomAD4 genome

AF:

0.355

AC:

54076

AN:

152160

Hom.:

10329

Cov.:

AF XY:

0.357

AC XY:

26555

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.241

Gnomad4 AMR

AF:

0.331

Gnomad4 ASJ

AF:

0.412

Gnomad4 EAS

AF:

0.177

Gnomad4 SAS

AF:

0.286

Gnomad4 FIN

AF:

0.490

Gnomad4 NFE

AF:

0.421

Gnomad4 OTH

AF:

0.355

Alfa

AF:

0.397

Hom.:

24645

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

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.21

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over