rs797045573

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001999.4(FBN2):​c.4461A>T​(p.Arg1487Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.566
Variant links:
Genes affected
FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
BP4
Computational evidence support a benign effect (MetaRNN=0.17827022).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN2NM_001999.4 linkuse as main transcriptc.4461A>T p.Arg1487Ser missense_variant 34/65 ENST00000262464.9 NP_001990.2
FBN2XM_017009228.3 linkuse as main transcriptc.4308A>T p.Arg1436Ser missense_variant 33/64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkuse as main transcriptc.4461A>T p.Arg1487Ser missense_variant 34/651 NM_001999.4 ENSP00000262464 P1P35556-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461818
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727200
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 testingGenetic Services Laboratory, University of ChicagoDec 01, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.062
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.64
D;.;D;D;D
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.84
T;.;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.18
T;T;T;T;T
MetaSVM
Uncertain
0.30
D
MutationAssessor
Benign
1.5
L;.;L;.;.
MutationTaster
Benign
0.99
D;N;N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.3
D;.;D;D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.013
D;.;D;D;D
Sift4G
Benign
0.54
.;.;.;T;T
Polyphen
0.037
B;.;B;.;D
Vest4
0.46
MutPred
0.41
Loss of catalytic residue at R1487 (P = 0.0099);.;Loss of catalytic residue at R1487 (P = 0.0099);.;.;
MVP
0.46
MPC
0.42
ClinPred
0.97
D
GERP RS
-4.6
Varity_R
0.33
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs797045573; hg19: chr5-127664398; API