rs1555398681

Positions:

• chr15-48488452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.3124G>A​(p.Gly1042Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1042D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a disulfide_bond (size 14) in uniprot entity FBN1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48488451-C-T is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 15-48488452-C-T is Pathogenic according to our data. Variant chr15-48488452-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48488452-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3124G>A	p.Gly1042Ser	missense_variant	26/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3124G>A	p.Gly1042Ser	missense_variant	25/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3124G>A	p.Gly1042Ser	missense_variant	26/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic (Clinvar ID: VCV000519571). A different missense change at the same codon (p.Gly1042Asp) has been reported to be associated with FBN1 related disorder (ClinVar ID: VCV000519740 / PMID: 16835936). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2020

The p.G1042S variant (also known as c.3124G>A), located in coding exon 25 of the FBN1 gene, results from a G to A substitution at nucleotide position 3124. The glycine at codon 1042 is replaced by serine, an amino acid with similar properties, and is located in the cb EGF-like #11 domain. This alteration was detected in a 30 year old female reported to have Marfan syndrome who had ectopia lentis, pectus carinatum, and pes planus (Attanasio M et al. Clin Genet. 2008;74:39-46). Another alteration affecting this amino acid (p.G1042D, c.3125G>A) was reported in a 2 year old patient who met major cardiovascular and skeletal criteria but who did not fulfill Ghent criteria at the time of study (Sakai H et al. Am J Med Genet A. 2006;140:1719-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1042 of the FBN1 protein (p.Gly1042Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBN1-related conditions (PMID: 18435798; Invitae). ClinVar contains an entry for this variant (Variation ID: 519571). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1042 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 16835936), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.83	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.080	T
Vest4		0.97
MutPred		0.83		Loss of ubiquitination at K1043 (P = 0.052);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1555398681; hg19: chr15-48780649; COSMIC: COSV57316029;