5-128408712-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001999.4(FBN2):​c.1040G>T​(p.Arg347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

4
10
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.81
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN2NM_001999.4 linkc.1040G>T p.Arg347Leu missense_variant 8/65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.1040G>T p.Arg347Leu missense_variant 8/64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.1040G>T p.Arg347Leu missense_variant 8/651 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000508989.5 linkc.941G>T p.Arg314Leu missense_variant 7/332 ENSP00000425596.1 D6RJI3
FBN2ENST00000508053.6 linkc.1040G>T p.Arg347Leu missense_variant 14/155 ENSP00000424571.2 A0A9H4AZX0
FBN2ENST00000703787.1 linkn.747G>T non_coding_transcript_exon_variant 7/10

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
250988
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135626
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:
0.0000462
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461740
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727174
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:
0.0000187
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;.;D;D
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.91
D;.;.;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
0.40
N;.;N;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.0
D;.;D;D
REVEL
Pathogenic
0.73
Sift
Benign
0.18
T;.;T;T
Sift4G
Benign
0.30
.;.;.;T
Polyphen
0.82
P;.;P;P
Vest4
0.88
MutPred
0.74
Gain of stability (P = 0.0386);.;Gain of stability (P = 0.0386);.;
MVP
0.95
MPC
0.55
ClinPred
0.80
D
GERP RS
4.9
Varity_R
0.25
gMVP
0.59

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: rs112428886; hg19: chr5-127744405; API