chr19-8065992-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032447.5(FBN3):​c.8357G>A​(p.Gly2786Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2786S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.328
Variant links:
Genes affected
FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.052482247).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBN3NM_032447.5 linkuse as main transcriptc.8357G>A p.Gly2786Asp missense_variant 64/64 ENST00000600128.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBN3ENST00000600128.6 linkuse as main transcriptc.8357G>A p.Gly2786Asp missense_variant 64/641 NM_032447.5
FBN3ENST00000270509.6 linkuse as main transcriptc.8357G>A p.Gly2786Asp missense_variant 63/631
FBN3ENST00000601739.5 linkuse as main transcriptc.8357G>A p.Gly2786Asp missense_variant 64/641
FBN3ENST00000651877.1 linkuse as main transcriptc.8483G>A p.Gly2828Asp missense_variant 64/64 P1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152264
Hom.:
0
Cov.:
33
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:
0.000385
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000242
AC:
6
AN:
247998
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1460570
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
726576
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152382
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74522
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Flexion contracture Uncertain:1
Uncertain significance, no assertion criteria providedresearchLupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine-- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 20, 2023This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2786 of the FBN3 protein (p.Gly2786Asp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN3 protein function. ClinVar contains an entry for this variant (Variation ID: 816791). This missense change has been observed in individual(s) with joint contractures (PMID: 26752647). This variant is present in population databases (rs760179129, gnomAD 0.01%). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
5.4
DANN
Benign
0.97
DEOGEN2
Benign
0.017
T;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.43
.;.;T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.052
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.6
L;L;L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.13
.;N;.
REVEL
Benign
0.092
Sift
Benign
0.62
.;T;.
Sift4G
Benign
0.69
T;T;T
Polyphen
0.0010
B;B;B
Vest4
0.067
MVP
0.49
MPC
0.25
ClinPred
0.026
T
GERP RS
-0.90
Varity_R
0.037
gMVP
0.63

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.

Other links and lift over

dbSNP: rs760179129; hg19: chr19-8130876; API