GeneBe

15-48412619-G-C

Variant names:
GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.
+3 Uncertain · Warm
-7
-6
-1
0
+5
+6
+9
+10
B
LB
VUS
LP
P
 The variant received 3 classification points (ACMG Germline Pathogenicity v2019): 3P and 0B. PM2PP2

The NM_000138.5(FBN1):c.8176C>G (p.Arg2726Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,880 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R2726L: Uncertain_significance (ClinVar VariationId 1302362, 1 star); p.R2726Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 237107); p.R2726W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 16445)

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

1
10
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

30 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • Weill-Marchesani syndrome 2, dominant
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • 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: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000138.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 points.

PM2
Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
PP2
Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 8.199). ClinVar shows strong pathogenic missense enrichment: 1743 P/LP and 288 B/LB missense entries (ratio 6.1×).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FBN1
NM_000138.5
MANE Select
c.8176C>Gp.Arg2726Gly
missense
Exon 65 of 66NP_000129.3
FBN1
NM_001406716.1
c.8176C>Gp.Arg2726Gly
missense
Exon 64 of 65NP_001393645.1P35555

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FBN1
ENST00000316623.10
TSL:1 MANE Select
c.8176C>Gp.Arg2726Gly
missense
Exon 65 of 66ENSP00000325527.5P35555
FBN1
ENST00000559133.6
TSL:1
n.*984C>G
3_prime_UTR
Exon 66 of 67ENSP00000453958.2H0YND0
FBN1
ENST00000559133.6
TSL:1
n.*984C>G
non_coding_transcript_exon
Exon 66 of 67ENSP00000453958.2H0YND0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111998
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.092
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.37
T
MetaSVM
Benign
-0.41
T
PhyloP100
2.1
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.5
D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.023
D
Mutation Taster
=58/42
polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

Other links and lift over

dbSNP: rs61746008;
hg19: chr15-48704816;
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