22-45541269-C-G

Variant summary

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

The NM_006486.3(FBLN1):​c.963C>G​(p.Ile321Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I321I) has been classified as Benign.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

FBLN1
NM_006486.3 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

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]

Genome browser will be placed here

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=0.14667487).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBLN1NM_006486.3 linkc.963C>G p.Ile321Met missense_variant Exon 9 of 17 ENST00000327858.11 NP_006477.3 P23142-1Q8NBH6
FBLN1NM_001996.4 linkc.963C>G p.Ile321Met missense_variant Exon 9 of 15 NP_001987.3 P23142-4A0A8S0LWY1
FBLN1NM_006485.4 linkc.963C>G p.Ile321Met missense_variant Exon 9 of 15 NP_006476.3 P23142-3Q8NBH6
FBLN1NM_006487.3 linkc.963C>G p.Ile321Met missense_variant Exon 9 of 15 NP_006478.3 P23142-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBLN1ENST00000327858.11 linkc.963C>G p.Ile321Met missense_variant Exon 9 of 17 1 NM_006486.3 ENSP00000331544.6 P23142-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152096
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251468
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461820
Hom.:
0
Cov.:
49
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152096
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
0.0030
DANN
Benign
0.92
DEOGEN2
Benign
0.34
.;.;T;.;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.60
T;T;T;T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.15
T;T;T;T;T
MetaSVM
Uncertain
-0.034
T
MutationAssessor
Benign
0.46
.;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.50
N;N;N;N;N
REVEL
Uncertain
0.37
Sift
Benign
0.11
T;T;T;T;T
Sift4G
Benign
0.11
T;T;T;T;T
Polyphen
0.76
P;P;P;.;.
Vest4
0.11
MutPred
0.53
Gain of glycosylation at S354 (P = 0.1405);.;.;.;.;
MVP
0.50
MPC
0.43
ClinPred
0.13
T
GERP RS
-11
Varity_R
0.028
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs9682; hg19: chr22-45937149; API