NM_000138.5:c.5284G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong

The NM_000138.5(FBN1):c.5284G>A(p.Gly1762Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 5.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 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.

PP5

Variant 15-48460258-C-T is Pathogenic according to our data. Variant chr15-48460258-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48460258-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-48460258-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.5284G>A	p.Gly1762Ser	missense_variant	Exon 43 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.5284G>A	p.Gly1762Ser	missense_variant	Exon 42 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.5284G>A	p.Gly1762Ser	missense_variant	Exon 43 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74392

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Sep 01, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1: PS2:Very Strong, PM1, PS4:Moderate, PP4 -

Apr 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 25979247, 24339047, 21683322, 29191498, 27935852, 29620724, 31350823, 32005694, 33030311, 34006472, 33082559) -

Geleophysic dysplasia 2

Pathogenic:4

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 08, 2021

Pars Genome Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

we found this variant in a 6-year-old girl with bone dysplasia. -

Apr 01, 2015

Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

May 16, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5284G>A (p.G1762S) alteration is located in exon 43 (coding exon 42) of the FBN1 gene. This alteration results from a G to A substitution at nucleotide position 5284, causing the glycine (G) at amino acid position 1762 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the FBN1 c.5284G>A (p.G1762S) alteration is classified as pathogenic for FBN1-related acromelic dysplasias; however, it is unlikely to be causative of either Marfan syndrome and related fibrillinopathies or Marfan lipodystrophy syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.5284G>A alteration has been previously reported as a recurrent de novo in multiple unrelated individuals with geleophysic dysplasia and acromelic dysplasia (Fan, 2021; Le Goff, 2011; Sun, 2020). Additionally, this alteration has been observed in heterozygous state in multiple other related and unrelated individuals with geleophysic and acromelic dysplasia (Cheng, 2018; Klein, 2014; Le Goff, 2011; Maddirevula, 2018; Marzin, 2021; Piccolo, 2019; Verberne, 2022). This amino acid position is highly conserved in available vertebrate species. Functional analysis by Jensen et al. (2015) demonstrated that the p.G1762S alteration resulted in normal or near normal protein secretion, consistent with other alterations associated with geleophysic dysplasia. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Acromicric dysplasia

Pathogenic:1

Dec 05, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029697 /PMID: 21683322). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 21683322). Different missense changes at the same codon (p.Gly1762Cys, p.Gly1762Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000392910, VCV001723869). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1762 of the FBN1 protein (p.Gly1762Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with geleophysic dysplasia (PMID: 21683322, 27935852, 29620724). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

-0.15

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0080

Sift4G

Benign

0.064

Vest4

0.63

MutPred

0.56

Loss of catalytic residue at G1762 (P = 0.0635);

MVP

0.86

MPC

0.55

ClinPred

0.99

GERP RS

5.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over