15-48463965-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000138.5(FBN1):​c.4999G>A​(p.Val1667Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.496
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a domain EGF-like 28; calcium-binding (size 40) in uniprot entity FBN1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000138.5
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.10962096).
BS2
High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN1NM_000138.5 linkuse as main transcriptc.4999G>A p.Val1667Ile missense_variant 41/66 ENST00000316623.10 NP_000129.3
FBN1NM_001406716.1 linkuse as main transcriptc.4999G>A p.Val1667Ile missense_variant 40/65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.4999G>A p.Val1667Ile missense_variant 41/661 NM_000138.5 ENSP00000325527 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251208
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461270
Hom.:
0
Cov.:
31
AF XY:
0.0000316
AC XY:
23
AN XY:
726966
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000602
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthNov 02, 2023This missense variant replaces valine with isoleucine at codon 1667 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome or a related connective tissue disorder (PMID: 10464652). This variant has been identified in 10/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 23, 2019The FBN1 c.4999G>A; p.Val1667Ile variant (rs140626) has been described in at least one individual affected with Marfan syndrome or a related connective tissue disorder (Liu 1997). It contains an entry in ClinVar (Variation ID: 406339) and is observed in the general population at a low overall frequency of 0.0035% (10/282608 alleles) in the Genome Aggregation Database. The valine at codon 1667 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to limited information regarding this variant, its clinical significance cannot be determined with certainty. REFERENCES Liu W et al. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test. 1997;1(4):237-42. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 07, 2023This missense variant replaces valine with isoleucine at codon 1667 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 10/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 16, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 11875032, 10464652, 11461921) -
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 24, 2022- -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
18
DANN
Uncertain
0.98
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.41
T
MutationTaster
Benign
0.79
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
0.13
N
REVEL
Benign
0.20
Sift
Benign
0.45
T
Sift4G
Benign
0.22
T
Vest4
0.11
MutPred
0.54
Loss of catalytic residue at V1667 (P = 0.1818);
MVP
0.23
MPC
0.45
ClinPred
0.081
T
GERP RS
3.7

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: rs140626; hg19: chr15-48756162; COSMIC: COSV57320973; API