rs776625874

chr15-48467958-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BP6 BS2

The NM_000138.5(FBN1):c.4727T>C(p.Met1576Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,068 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1576I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 1.32

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2792021).
• BP6: Variant 15-48467958-A-G is Benign according to our data. Variant chr15-48467958-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200054.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}. Variant chr15-48467958-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4727T>C	p.Met1576Thr	missense_variant	38/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4727T>C	p.Met1576Thr	missense_variant	37/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4727T>C	p.Met1576Thr	missense_variant	38/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152226 Hom.: 0 Cov.: 32

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251284 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.000261 AC XY: 190 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000187

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74370

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: 0.0000941

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2023	This missense variant replaces methionine with threonine at codon 1576 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 and in an individual who presented with isolated dilatation of the ascending aorta (PMID: 16220557), as well as in an individual affected with suspected Marfan syndrome or related fibrillinopathy (PMID: 31163209). This variant has been identified in three individuals affected with idiopathic scoliosis, one of whom was studied in detail and did not show symptoms associated with Marfan syndrome (PMID: 24833718). This variant has also been identified in 34/282694 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 2 papers, associated with Marfan syndrome. It is present in one individual with isolated dilation of the ascending aorta and one with Marfan syndrome. It is classified in ClinVar with 2 stars as VUS by GeneDx and Invitae. The variant has a Max MAF in ExAC of 0.015% (10 alleles) and in gnomAD of 0.02% (31 alleles). Max prevalence of Marfan is 1/3000. This AA is not conserved and Zebra Finch has a Thr at this position. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: FBN1 c.4727T>C (p.Met1576Thr) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 252050 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4727T>C has been reported in the literature in at least one individual with an unknown bicuspid aortic valve phenotype (e.g. Gillis_2017). The variant has also been reported in the literature in individuals with Adolescent Idiopathic Scoliosis and suspected Marfan Syndrome (e.g. Rommel_2005, Rybczynski_2008, Sheikhzadeh_2012, Buchan_2014, Madar_2019, Damrauer_2019). Several of the individuals described in these reports underwent clinical genetics evaluations and had a normal range of Ghent systemic features (4 to 5 points, e.g. Buchan_2014, Madar_2019) or were reported without cardiac involvement (e.g. Damrauer_2019). The patients described by Buchan et al. were reported to have normal echocardiograms and ophthalmological evaluations, and no family history of aortic aneurysm or scoliosis, therefore suggesting possible lack of co-segregation with disease. These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24833718, 31211626, 28659821, 26333736, 31163209, 16220557, 19012347, 21883168). Eight ClinVar submitters (evaluation after 2014) have cited the variant; seven submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2023	Reported in at least two individuals with aortic dilation/dissection (PMID: 16220557, 19012347, 21883168), as well as individuals with a Marfan-related phenotype (PMID: 31211626, 31163209); Reported in individuals with severe adolescent idiopathic scoliosis (PMID: 24833718, 26333736); In silico analysis supports that this missense variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 31211626, 26333736, 21883168, 19012347, 29935118, 31163209, 28659821, 12938084, 24833718, 16220557) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2020	- -

Marfan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces methionine with threonine at codon 1576 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 and in an individual with unknown family history who presented with isolated dilatation of the ascending aorta (PMID: 16220557). This variant has also been identified in three individuals affected with idiopathic scoliosis (PMID: 24833718), one of whom was studied in detail and did not show symptoms associated with Marfan syndrome. This variant has been observed in an individual affected with suspected Marfan syndrome or related fibrillinopathy. This variant has also been identified in 34/282694 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. -

FBN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The FBN1 c.4727T>C variant is predicted to result in the amino acid substitution p.Met1576Thr. This variant has been reported in the heterozygous state in patients with aortic dissection/dilation (Rommel et al. 2005. PubMed ID: 16220557 and Sheikhzadeh et al. 2012. PubMed ID: 21883168), an individual undergoing testing for suspected Marfan syndrome (Rybczynski et al. 2008. PubMed ID: 19012347), as well as patients with adolescent idiopathic scoliosis (Buchan et al. 2014. PubMed ID: 24833718 and Haller et al. 2015. PubMed ID: 26333736). To our knowledge, no functional studies were performed to help assess the pathogenicity of this variant. This variant has been documented in 34 heterozygous individuals in gnomAD and was interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/200054/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	18
Dann	Benign	0.84
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.37	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.46
Sift	Benign	0.44	T
Sift4G	Benign	0.36	T
Vest4		0.20
MVP		0.91
MPC		0.58
ClinPred		0.046	T
GERP RS		5.1

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

Other links and lift over

dbSNP: rs776625874; hg19: chr15-48760155;