rs363823

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000138.5(FBN1):​c.6617-21A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,612,404 control chromosomes in the GnomAD database, including 777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point.. The gene FBN1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.029 ( 97 hom., cov: 32)
Exomes 𝑓: 0.022 ( 680 hom. )

Consequence

FBN1
NM_000138.5 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.20

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4
This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 15-48433009-T-A is Benign according to our data. Variant chr15-48433009-T-A is described in ClinVar as Benign. ClinVar VariationId is 255308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

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.6617-21A>T
intron
N/ANP_000129.3
FBN1
NM_001406716.1
c.6617-21A>T
intron
N/ANP_001393645.1P35555

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FBN1
ENST00000316623.10
TSL:1 MANE Select
c.6617-21A>T
intron
N/AENSP00000325527.5P35555
FBN1
ENST00000559133.6
TSL:1
n.6617-21A>T
intron
N/AENSP00000453958.2H0YND0
FBN1
ENST00000537463.6
TSL:5
n.*2380-21A>T
intron
N/AENSP00000440294.2F6U495

Frequencies

GnomAD3 genomes
AF:
0.0288
AC:
4374
AN:
152026
Hom.:
96
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0399
Gnomad AMI
AF:
0.0980
Gnomad AMR
AF:
0.0383
Gnomad ASJ
AF:
0.0139
Gnomad EAS
AF:
0.0818
Gnomad SAS
AF:
0.0469
Gnomad FIN
AF:
0.0172
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0162
Gnomad OTH
AF:
0.0287
GnomAD2 exomes
AF:
0.0299
AC:
7479
AN:
250426
AF XY:
0.0281
show subpopulations
Gnomad AFR exome
AF:
0.0400
Gnomad AMR exome
AF:
0.0540
Gnomad ASJ exome
AF:
0.0144
Gnomad EAS exome
AF:
0.0741
Gnomad FIN exome
AF:
0.0135
Gnomad NFE exome
AF:
0.0154
Gnomad OTH exome
AF:
0.0314
GnomAD4 exome
AF:
0.0223
AC:
32497
AN:
1460260
Hom.:
680
Cov.:
32
AF XY:
0.0223
AC XY:
16219
AN XY:
726426
show subpopulations
African (AFR)
AF:
0.0396
AC:
1324
AN:
33404
American (AMR)
AF:
0.0537
AC:
2399
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
0.0159
AC:
416
AN:
26088
East Asian (EAS)
AF:
0.107
AC:
4231
AN:
39664
South Asian (SAS)
AF:
0.0357
AC:
3076
AN:
86244
European-Finnish (FIN)
AF:
0.0146
AC:
774
AN:
53014
Middle Eastern (MID)
AF:
0.0260
AC:
150
AN:
5760
European-Non Finnish (NFE)
AF:
0.0166
AC:
18410
AN:
1111092
Other (OTH)
AF:
0.0285
AC:
1717
AN:
60312
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
1455
2910
4364
5819
7274
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
838
1676
2514
3352
4190
<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:
0.0288
AC:
4386
AN:
152144
Hom.:
97
Cov.:
32
AF XY:
0.0298
AC XY:
2220
AN XY:
74390
show subpopulations
African (AFR)
AF:
0.0400
AC:
1659
AN:
41484
American (AMR)
AF:
0.0385
AC:
588
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.0139
AC:
48
AN:
3464
East Asian (EAS)
AF:
0.0820
AC:
425
AN:
5184
South Asian (SAS)
AF:
0.0474
AC:
228
AN:
4814
European-Finnish (FIN)
AF:
0.0172
AC:
182
AN:
10600
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.0162
AC:
1103
AN:
68004
Other (OTH)
AF:
0.0284
AC:
60
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
217
433
650
866
1083
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
48
96
144
192
240
<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:
0.0207
Hom.:
4
Bravo
AF:
0.0315
Asia WGS
AF:
0.0710
AC:
248
AN:
3478

ClinVar

ClinVar submissions
Significance:Benign
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
2
not provided (2)
-
-
2
not specified (2)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
5.2
DANN
Benign
0.58
PhyloP100
1.2
La Branchor
0.72
BranchPoint Hunter
3.0
Mutation Taster
=100/0
polymorphism (auto)

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: rs363823; hg19: chr15-48725206; COSMIC: COSV57312418; COSMIC: COSV57312418; 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.