chr19-8066127-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032447.5(FBN3):ā€‹c.8222T>Cā€‹(p.Ile2741Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Synonymous variant affecting the same amino acid position (i.e. I2741I) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

FBN3
NM_032447.5 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.83
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBN3NM_032447.5 linkuse as main transcriptc.8222T>C p.Ile2741Thr missense_variant 64/64 ENST00000600128.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBN3ENST00000600128.6 linkuse as main transcriptc.8222T>C p.Ile2741Thr missense_variant 64/641 NM_032447.5
FBN3ENST00000270509.6 linkuse as main transcriptc.8222T>C p.Ile2741Thr missense_variant 63/631
FBN3ENST00000601739.5 linkuse as main transcriptc.8222T>C p.Ile2741Thr missense_variant 64/641
FBN3ENST00000651877.1 linkuse as main transcriptc.8348T>C p.Ile2783Thr missense_variant 64/64 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152226
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461202
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726918
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 04, 2023The c.8222T>C (p.I2741T) alteration is located in exon 63 (coding exon 63) of the FBN3 gene. This alteration results from a T to C substitution at nucleotide position 8222, causing the isoleucine (I) at amino acid position 2741 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T;T;T
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
.;.;D
M_CAP
Benign
0.052
D
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Uncertain
2.7
M;M;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-4.1
.;D;.
REVEL
Uncertain
0.62
Sift
Uncertain
0.0010
.;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.80
P;P;P
Vest4
0.59
MutPred
0.60
Loss of stability (P = 0.0106);Loss of stability (P = 0.0106);Loss of stability (P = 0.0106);
MVP
0.82
MPC
0.73
ClinPred
0.99
D
GERP RS
4.5
Varity_R
0.55
gMVP
0.84

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: rs2081384615; hg19: chr19-8131011; API