Genetic Variant FBLN1:p.Ala21Glu (chr22-45503047-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006486.3(FBLN1):c.62C>A(p.Ala21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBLN1
NM_006486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.198

Publications

0 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: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

FBLN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29028606).

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.62C>A	p.Ala21Glu	missense	Exon 1 of 17	NP_006477.3
FBLN1	NM_001996.4		c.62C>A	p.Ala21Glu	missense	Exon 1 of 15	NP_001987.3
FBLN1	NM_006485.4		c.62C>A	p.Ala21Glu	missense	Exon 1 of 15	NP_006476.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.62C>A	p.Ala21Glu	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
FBLN1	ENST00000262722.11	TSL:1	c.62C>A	p.Ala21Glu	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
FBLN1	ENST00000442170.6	TSL:1	c.62C>A	p.Ala21Glu	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1098046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

524532

African (AFR)

AF:

0.00

AC:

AN:

22870

American (AMR)

AF:

0.00

AC:

AN:

10298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14906

East Asian (EAS)

AF:

0.00

AC:

AN:

25970

South Asian (SAS)

AF:

0.00

AC:

AN:

25654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3106

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

929476

Other (OTH)

AF:

0.00

AC:

AN:

43734

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.052

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.34

PhyloP100

0.20

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.070

REVEL

Benign

0.24

Sift

Benign

0.039

Sift4G

Benign

0.11

Polyphen

0.16

Vest4

0.095

MutPred

0.64

Gain of loop (P = 0.0166)

MVP

0.60

MPC

0.45

ClinPred

0.16

GERP RS

1.7

PromoterAI

0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.096

gMVP

0.38

Mutation Taster

=67/33

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over