Variant chr22-45503017-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006486.3(FBLN1):c.32C>A(p.Pro11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,247,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

FBLN1
NM_006486.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0300

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=0.25621688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FBLN1	NM_006486.3 linkuse as main transcript	c.32C>A	p.Pro11Gln	missense_variant	1/17	ENST00000327858.11
FBLN1	NM_001996.4 linkuse as main transcript	c.32C>A	p.Pro11Gln	missense_variant	1/15
FBLN1	NM_006485.4 linkuse as main transcript	c.32C>A	p.Pro11Gln	missense_variant	1/15
FBLN1	NM_006487.3 linkuse as main transcript	c.32C>A	p.Pro11Gln	missense_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN1	ENST00000327858.11 linkuse as main transcript	c.32C>A	p.Pro11Gln	missense_variant	1/17	1	NM_006486.3	P1	P23142-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095858

Hom.:

Cov.:

AF XY:

0.00000190

AC XY:

AN XY:

525400

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:

0.00000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151396

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73962

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Synpolydactyly type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 03, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.051

T;.;.;T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.69

T;T;T;T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.55

.;.;N;N;N;N

MutationTaster

Benign

0.99

N;N;N;N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.65

N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.036

D;T;T;T;D;D

Polyphen

0.54, 0.53, 0.40

.;P;P;B;.;.

Vest4

0.16, 0.11, 0.17, 0.25, 0.18

MutPred

0.52

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);

MVP

0.56

MPC

0.36

ClinPred

0.26

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.089

gMVP

0.42

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