rs146166400

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1

The NM_000138.5(FBN1):​c.7346A>G​(p.Asn2449Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene FBN1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

4
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.611

Publications

7 publications found
Variant links:
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
FBN1 Gene-Disease associations (from GenCC):
  • Marfan syndrome
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Acromicric dysplasia
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
  • progeroid and marfanoid aspect-lipodystrophy syndrome
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • stiff skin syndrome
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Weill-Marchesani syndrome 2, dominant
    Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • geleophysic dysplasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • isolated ectopia lentis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • neonatal Marfan syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Weill-Marchesani syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • ectopia lentis 1, isolated, autosomal dominant
    Inheritance: AD Classification: LIMITED Submitted by: G2P
  • Shprintzen-Goldberg syndrome
    Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1
In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000138.5
PP2
Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Weill-Marchesani syndrome 2, dominant, Acromicric dysplasia, isolated ectopia lentis, progeroid and marfanoid aspect-lipodystrophy syndrome, Marfan syndrome, stiff skin syndrome, Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection, ectopia lentis 1, isolated, autosomal dominant, Weill-Marchesani syndrome, neonatal Marfan syndrome, geleophysic dysplasia.
BP4
Computational evidence support a benign effect (MetaRNN=0.02113232).
BP6
Variant 15-48425476-T-C is Benign according to our data. Variant chr15-48425476-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42425.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00044 (67/152330) while in subpopulation AFR AF = 0.00156 (65/41572). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FBN1
NM_000138.5
MANE Select
c.7346A>Gp.Asn2449Ser
missense
Exon 60 of 66NP_000129.3
FBN1
NM_001406716.1
c.7346A>Gp.Asn2449Ser
missense
Exon 59 of 65NP_001393645.1P35555

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FBN1
ENST00000316623.10
TSL:1 MANE Select
c.7346A>Gp.Asn2449Ser
missense
Exon 60 of 66ENSP00000325527.5P35555
FBN1
ENST00000559133.6
TSL:1
n.*154A>G
non_coding_transcript_exon
Exon 61 of 67ENSP00000453958.2H0YND0
FBN1
ENST00000559133.6
TSL:1
n.*154A>G
3_prime_UTR
Exon 61 of 67ENSP00000453958.2H0YND0

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
67
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00157
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000836
AC:
21
AN:
251092
AF XY:
0.0000590
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS 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:
0.0000369
AC:
54
AN:
1461824
Hom.:
1
Cov.:
32
AF XY:
0.0000413
AC XY:
30
AN XY:
727214
show subpopulations
African (AFR)
AF:
0.00140
AC:
47
AN:
33476
American (AMR)
AF:
0.0000224
AC:
1
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111978
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000440
AC:
67
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.000389
AC XY:
29
AN XY:
74502
show subpopulations
African (AFR)
AF:
0.00156
AC:
65
AN:
41572
American (AMR)
AF:
0.000131
AC:
2
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000186
Hom.:
0
Bravo
AF:
0.000559
ESP6500AA
AF:
0.00114
AC:
5
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000123
AC:
15

ClinVar

ClinVar submissions
Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
2
Familial thoracic aortic aneurysm and aortic dissection (3)
-
-
2
not provided (2)
-
1
1
not specified (2)
-
1
-
Marfan syndrome (1)
-
-
1
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
14
DANN
Benign
0.32
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.39
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.021
T
MetaSVM
Benign
-0.56
T
PhyloP100
0.61
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.55
N
REVEL
Uncertain
0.38
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Vest4
0.14
MVP
0.39
MPC
0.40
ClinPred
0.013
T
GERP RS
4.8
Mutation Taster
=72/28
polymorphism

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

Other links and lift over

dbSNP: rs146166400; hg19: chr15-48717673; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.