rs150224718

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001999.4(FBN2):​c.3464A>G​(p.Asn1155Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.00012 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

1
8
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.01
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 Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 170 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.3464A>G p.Asn1155Ser missense_variant Exon 26 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.3311A>G p.Asn1104Ser missense_variant Exon 25 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.3464A>G p.Asn1155Ser missense_variant Exon 26 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152192
Hom.:
0
Cov.:
32
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251414
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000116
AC:
170
AN:
1461744
Hom.:
0
Cov.:
31
AF XY:
0.000102
AC XY:
74
AN XY:
727180
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:
0.000151
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74490
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Feb 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.N1155S variant (also known as c.3464A>G), located in coding exon 26 of the FBN2 gene, results from an A to G substitution at nucleotide position 3464. The asparagine at codon 1155 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Nov 11, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1
Aug 09, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:1
Sep 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;D;T;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;.;.;T;T
M_CAP
Benign
0.054
D
MetaRNN
Uncertain
0.66
D;D;D;D;D
MetaSVM
Uncertain
-0.075
T
MutationAssessor
Benign
-0.48
N;.;N;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.6
D;.;D;D;D
REVEL
Uncertain
0.47
Sift
Benign
0.45
T;.;T;T;T
Sift4G
Benign
0.21
.;.;.;T;T
Polyphen
1.0
D;.;D;.;P
Vest4
0.85
MVP
0.49
MPC
0.29
ClinPred
0.60
D
GERP RS
5.1
Varity_R
0.25
gMVP
0.72

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: rs150224718; hg19: chr5-127674633; API