rs142888621

chr15-48526216-C-Achr15-48526216-C-Gchr15-48526216-C-T

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.902G>T(p.Gly301Val) variant causes a missense change. The variant allele was found at a frequency of 0.000252 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G301A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (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:7 B:12
• Conservation: PhyloP100: 3.98

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]

LOC124903488 (HGNC:):

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, 9 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.34140205).
• BP6: Variant 15-48526216-C-A is Benign according to our data. Variant chr15-48526216-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199960.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=8, Uncertain_significance=6}. Variant chr15-48526216-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.902G>T	p.Gly301Val	missense_variant	9/66	ENST00000316623.10
FBN1	NM_001406716.1	c.902G>T	p.Gly301Val	missense_variant	8/65
LOC124903488	XR_007064628.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.902G>T	p.Gly301Val	missense_variant	9/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.902G>T	p.Gly301Val	missense_variant, NMD_transcript_variant	9/67	1
FBN1	ENST00000674301.2	c.902G>T	p.Gly301Val	missense_variant, NMD_transcript_variant	9/68
FBN1	ENST00000537463.6	c.636+11495G>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 251426 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135884

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000260 AC: 380 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 197 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74456

Gnomad4 AFR AF: 0.0000963

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: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	This variant is associated with the following publications: (PMID: 26188975, 26787436, 28655553, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2022	The FBN1 c.902G>T, p.Gly301Val variant (rs142888621; ClinVar variation ID: 199960), has been detected in three patient cohorts composed of Marfan, vascular anomaly, TAAD patients (Franken 2016, Mattassi 2018, Ziganshin 2015); however, direct evidence of pathogenicity is not provided. This variant is found in the general population with an overall allele frequency of 0.02% (51/282,816 alleles) in the Genome Aggregation Database. The glycine at codon 301 is located in the second EGF domain, though is not considered a consensus residue. Overall, this residue is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.372). Based on the available information, the clinical significance of this variant is uncertain. References: Franken et al. Genotype impacts survival in Marfan syndrome. Eur Heart J. 2016 Nov 14;37(43):3285-3290. PMID: 26787436 Mattassi et al. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg. 2018 Mar;67(3):922-932. PMID: 28655553 Ziganshin et al. Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov;100(5):1604-11. PMID: 26188975 -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 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	Apr 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2019	Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 2 Marfan probands (PubMed: 26787436). Computational tools predict benign. Identified in 0.04% of European chromosoems in gnomAD. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2019	Variant summary: FBN1 c.902G>T (p.Gly301Val) results in a non-conservative amino acid change located in the EGF-like domain 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 0.00019 in 277146 control chromosomes, predominantly at a frequency of 0.00036 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 3 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.902G>T has been reported in the literature in individuals affected with Marfan Syndrome, vascular anomalies and ascending aortic aneurysm (Mattassi_2018, Franken_2016, Ziganshin_2015). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as likely benign (1x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign. -

Marfan syndrome Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Jul 26, 2022

This variant has been reported in the literature in at least four individuals with various phenotypes including Marfan syndrome, thoracic aortic aneurysm and dissection, and vascular anomalies (Ziganshin 2015 PMID:26188975; Franken 2016 PMID:26787436; Mattassi 2017 PMID:28655553). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.035% [45/129138]; https://gnomad.broadinstitute.org/variant/15-48818413-C-A?dataset=gnomad_r2_1). This variant is also present in ClinVar (Variation ID:199960). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Stiff skin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Geleophysic dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Acromicric dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Ectopia lentis 1, isolated, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.094
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.21	T
Sift4G	Benign	0.093	T
Vest4		0.70
MVP		0.61
MPC		0.80
ClinPred		0.058	T
GERP RS		5.6

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: rs142888621; hg19: chr15-48818413;