chr15-48468045-G-A

Position:

• chr15-48468045-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.4640C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by isoleucine at amino acid 1547 (p.Thr1547Ile). This variant was found one proband with Marfan syndrome (PMID 24793577) and in three apparently unrelated probands with features of Marfan syndrome (PMID 24793577, internal data). In one of these individuals with features of Marfan syndrome, this variant was also detected in the proband’s mother and sister, both of whom had a systemic score of 9, however relatedness of these individuals was not confirmed (internal data). This variant was also identified in an individual with features of Marfan syndrome but no diagnosis who also carried a pathogenic variant in FBN1, c.3193delG p.Glu1065Lysfs*23 (PMID 29543232). The variant in FBN1 has been reported 17 times in ClinVar: 6 times as uncertain significance and 11 times as likely benign (Variation ID: 42367). This variant has been identified in 37 individuals of Latino/Admixed American origin in gnomAD v3.1.2 (MAF: 0.24%) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.375). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA015264/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign reviewed by expert panel U:7 B:13
• Conservation: PhyloP100: 2.61

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 Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4640C>T	p.Thr1547Ile	missense_variant	38/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4640C>T	p.Thr1547Ile	missense_variant	37/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4640C>T	p.Thr1547Ile	missense_variant	38/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251284 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000714

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:7 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with isoleucine at codon 1547 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 performed for this variant. This variant has been reported in an individual with suspected Marfan syndrome (PMID: 24793577) and in an individual with aneurysm of the thoracic aorta (PMID: 29543232). This variant has been identified in 9/282682 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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Jun 15, 2023	The NM_00138 c.4640C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by isoleucine at amino acid 1547 (p.Thr1547Ile). This variant was found one proband with Marfan syndrome (PMID 24793577) and in three apparently unrelated probands with features of Marfan syndrome (PMID 24793577, internal data). In one of these individuals with features of Marfan syndrome, this variant was also detected in the proband’s mother and sister, both of whom had a systemic score of 9, however relatedness of these individuals was not confirmed (internal data). This variant was also identified in an individual with features of Marfan syndrome but no diagnosis who also carried a pathogenic variant in FBN1, c.3193delG p.Glu1065Lysfs*23 (PMID 29543232). The variant in FBN1 has been reported 17 times in ClinVar: 6 times as uncertain significance and 11 times as likely benign (Variation ID: 42367). This variant has been identified in 37 individuals of Latino/Admixed American origin in gnomAD v3.1.2 (MAF: 0.24%) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.375). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1. -

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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2023	This missense variant replaces threonine with isoleucine at codon 1547 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 performed for this variant. This variant has been reported in an individual with suspected Marfan syndrome (PMID: 24793577) and in an individual with aneurysm of the thoracic aorta (PMID: 29543232). This variant has been identified in 9/282682 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2022	The p.T1547I variant (also known as c.4640C>T), located in coding exon 37 of the FBN1 gene, results from a C to T substitution at nucleotide position 4640. The threonine at codon 1547 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a subject with features of Marfan syndrome (Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	This variant is associated with the following publications: (PMID: 31227806, 29543232, 24793577) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2024	Variant summary: FBN1 c.4640C>T (p.Thr1547Ile) results in a non-conservative amino acid change located in the TGF-beta binding (TB) domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 1614156 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 8.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.4640C>T has been reported in the literature in a Latino individual suspected of Marfan Syndrome based on the old Ghent criteria (Lerner-Ellis_ 2014). The variant was also reported in a patient with aortic aneurysm who also carried a truncating FBN1 variant (FBN1 c.3193delG, p.Glu1065fsX23) that could explain the phenotype (Weerakkody_2018). 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: 24793577, 29543232). ClinVar contains an entry for this variant (Variation ID: 42367). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 16, 2024	The p.Thr1547Ile variant in FBN1 is classified as benign because it has been identified in 0.2% (37/15268) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant was classified as Benign on Jun 15, 2023 by the ClinGen-approved FBN1 Variant Curation expert panel (Variation ID 42367). ACMG/AMP Criteria applied: BA1. -

FBN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2023

The FBN1 c.4640C>T variant is predicted to result in the amino acid substitution p.Thr1547Ile. This variant has been reported in individuals with Marfan syndrome or features of Marfan syndrome (Tables S1 and S6, Lerner-Ellis et al. 2014. PubMed ID: 24793577; Supplementary Tables, Weerakkody et al. 2018. PubMed ID: 29543232; Table S1, Baudhuin et al. 2019. PubMed ID: 31227806). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48760242-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, raning from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/42367/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ectopia lentis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stiff skin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MASS syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Geleophysic dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Acromicric dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.92
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	0.93	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.62	N
REVEL	Uncertain	0.38
Sift	Benign	0.85	T
Sift4G	Benign	0.43	T
Vest4		0.26
MVP		0.55
MPC		0.54
ClinPred		0.052	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: rs183306990; hg19: chr15-48760242;