dbSNP rs1434686879: FBLN1:p.Leu20Ile (chr22-45503043-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006486.3(FBLN1):c.58C>A(p.Leu20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000909 in 1,099,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

FBLN1
NM_006486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.356

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23050594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3 link	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 17	ENST00000327858.11	NP_006477.3	P23142-1Q8NBH6
FBLN1	NM_001996.4 link	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 15		NP_001987.3	P23142-4A0A8S0LWY1
FBLN1	NM_006485.4 link	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 15		NP_006476.3	P23142-3Q8NBH6
FBLN1	NM_006487.3 link	c.58C>A	p.Leu20Ile	missense_variant	Exon 1 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.58C>A	p.Leu20Ile	missense_variant	Exon 1 of 17	1	NM_006486.3	ENSP00000331544.6		P23142-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.09e-7

AC:

AN:

1099572

Hom.:

Cov.:

AF XY:

0.00000190

AC XY:

AN XY:

525446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000107

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.058

T;.;.;T;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.62

T;T;T;T;T;T

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.69

.;.;N;N;N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.24

N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.24

T;T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.036, 0.025, 0.014

.;B;B;B;.;.

Vest4

0.20, 0.25, 0.22, 0.22, 0.21

MutPred

0.67

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.38

MPC

0.42

ClinPred

0.084

GERP RS

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.061

gMVP

0.23

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over