rs363836

chr15-48430687-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000138.5(FBN1):c.6855T>C(p.Asp2285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,613,772 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (97 hom., cov: 32)
  • Exomes 𝑓: 0.022 (679 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.96

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-48430687-A-G is Benign according to our data. Variant chr15-48430687-A-G is described in ClinVar as [Benign]. Clinvar id is 42412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48430687-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.6855T>C	p.Asp2285=	synonymous_variant	56/66	ENST00000316623.10
FBN1	NM_001406716.1	c.6855T>C	p.Asp2285=	synonymous_variant	55/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.6855T>C	p.Asp2285=	synonymous_variant	56/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.6855T>C	p.Asp2285=	synonymous_variant, NMD_transcript_variant	56/67	1
FBN1	ENST00000682170.1	n.464T>C		non_coding_transcript_exon_variant	4/13
FBN1	ENST00000674301.2	c.*306T>C		3_prime_UTR_variant, NMD_transcript_variant	57/68

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4378 AN: 152140 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0298 AC: 7500 AN: 251296 Hom.: 210 AF XY: 0.0280 AC XY: 3807 AN XY: 135804

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.0540

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0741

Gnomad SAS exome AF: 0.0402

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0223 AC: 32550 AN: 1461514 Hom.: 679 Cov.: 32 AF XY: 0.0223 AC XY: 16239 AN XY: 727078

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0288 AC: 4391 AN: 152258 Hom.: 97 Cov.: 32 AF XY: 0.0298 AC XY: 2217 AN XY: 74430

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.0384

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.0814

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0219 Hom.: 35

Bravo AF: 0.0315

Asia WGS AF: 0.0710 AC: 248 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 11, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Stiff skin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Geleophysic dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Ectopia lentis 1, isolated, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.024
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs363836; hg19: chr15-48722884; COSMIC: COSV57318304; COSMIC: COSV57318304;