rs137854475

chr15-48487155-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000138.5(FBN1):c.3509G>A(p.Arg1170His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,138 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1170C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:7 B:24 O:1
• Conservation: PhyloP100: 2.10

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 -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.04935786).
• BP6: Variant 15-48487155-C-T is Benign according to our data. Variant chr15-48487155-C-T is described in ClinVar as [Benign]. Clinvar id is 16451.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-48487155-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00164 (250/152258) while in subpopulation AMR AF= 0.00255 (39/15278). AF 95% confidence interval is 0.00219. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.3509G>A	p.Arg1170His	missense_variant	29/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3509G>A	p.Arg1170His	missense_variant	28/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3509G>A	p.Arg1170His	missense_variant	29/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00126 AC: 316 AN: 251438 Hom.: 0 AF XY: 0.00133 AC XY: 181 AN XY: 135894

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00245 AC: 3584 AN: 1461880 Hom.: 4 Cov.: 31 AF XY: 0.00241 AC XY: 1754 AN XY: 727244

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00303

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74454

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00219

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Uncertain:7 Benign:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1 Uncertain:3 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Benign, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Feb 01, 2023	The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). 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, BP2, BP5. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely pathogenic, flagged submission	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FBN1: BS1 -

not specified Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2021	Variant summary: FBN1 c.3509G>A (p.Arg1170His) results in a non-conservative amino acid change located in one of the EGF-like calcium-binding domains (IPR001881) 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 0.0014 in 396164 control chromosomes in the gnomAD database (version 2.1 and 3.1 datasets), including 1 homozygote. The observed variant frequency is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. c.3509G>A has been reported in the literature in cohorts of individuals affected with Marfan Syndrome or Marfan-like syndrome (e.g. Hayward_1994, Montgomery_1998, Comeglio_2007, Robinson_2011, Howarth_2007, Waldmuller_2007, Volk_2014, Franken_2016), however, in some of these studies an incomplete Marfan phenotype was noted, or no exact phenotype information was provided. In a recent case-control study the variant was found in 11 cases of imaging supported nonsyndromic aortopathy and/or mitral valve disease, and in 14 carriers without cardiovascular disease, whereas only 12/101 (12%) of controls without pathogenic FBN1 variants (with sufficient imaging), had evidence of mitral valve or aortic disease in this study (Damrauer_2019). Co-occurrences with other pathogenic variants have been reported (FBN1 c.4913delA, p.Tyr1638fsX2 and FBN1 c.1633C>T, p.Arg545Cys, in internal LCA samples), providing supporting evidence for a benign role. Two publications reported that the variant had no effect on splicing examining blood RNA samples (Robinson_2011, Wai_2020), however these data do not allow any conclusion for the protein level effect of the variant. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 mostly without evidence for independent evaluation, and classified the variant as VUS (n=5), or likely benign (n=10). Based on the evidence outlined above, though the variant could be associated with an increased risk for nonsyndromic aortopathy and/or mitral valve disease, it was classified for the Marfan Syndrome phenotype as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 24, 2015	p.Arg1170His in exon 28 of FBN1: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (124/66684) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs137854475). Arginine (Arg) at position 1170 is not conserved in evolut ionarily distant species and at least 10 birds, reptiles, and fish carry a histi dine (His) at this position, supporting that this change may be tolerated. This variant has been identified by our laboratory in 6 individuals with features of Marfan syndrome; however, two of these individuals were compound heterozygotes f or a pathogenic variant sufficient to explain their disease. Although this varia nt has been reported in individuals with features of Marfan syndrome in the lite rature, this variant is likely benign based on its frequency in the general popu lation, lack of conservation, and the presence of other variants to explain dise ase in multiple individuals. -

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 21, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MASS syndrome Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Dec 01, 1998

- -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FBN1 NM_000138.4 exon 29 p.Arg1170His (c.3509G>A): This variant has been reported in at least four individuals with incomplete/suspected Marfan syndrome, segregating with suspected features in at least two different families (Hayward 1994 PMID:7870075, Montgomery 1998 PMID:9837823, Comeglio 2007 PMID:17657824, Stavropoulos 2016 PMID:28567303). Of note, these reported probands presented with primarily skeletal abnormalities; none fully met Ghent criteria for Marfan syndrome. Additionally, this variant did not segregate with disease in one family with suspected Marfan syndrome that was tested in our lab. This variant is present in 0.2% (286/129170) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-48779352-C-T) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:16451). This variant amino acid Histidine (His) is present in several bird species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Disproportionate tall stature Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 25, 2014

- -

Acromicric dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Stiff skin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Geleophysic dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

FBN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ectopia lentis 1, isolated, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Ectopia lentis;C0024796:Marfan syndrome;C0265313:Weill-Marchesani syndrome;C0345050:Congenital aneurysm of ascending aorta;C1858556:MASS syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Likely benign and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.060
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.049	T
MetaSVM	Uncertain	-0.053	T
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Vest4		0.15
MVP		0.98
MPC		0.63
ClinPred		0.012	T
GERP RS		5.3

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: rs137854475; hg19: chr15-48779352; COSMIC: COSV57331178;