15-48472617-G-C

Position:

chr15-48472617-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 5P and 9B. PM1PM5PP2BP6BS1BS2

The NM_000138.5(FBN1):c.4270C>G(p.Pro1424Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P1424L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:9

Conservation

PhyloP100: 8.00

Variant links:

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]

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000138.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-48472617-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1073640.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, FBN1

BP6

Variant 15-48472617-G-C is Benign according to our data. Variant chr15-48472617-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42355.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=11, Benign=6}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000309 (47/152160) while in subpopulation AMR AF= 0.00203 (31/15280). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.4270C>G	p.Pro1424Ala	missense_variant	35/66	ENST00000316623.10
FBN1	NM_001406716.1 linkuse as main transcript	c.4270C>G	p.Pro1424Ala	missense_variant	34/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.4270C>G	p.Pro1424Ala	missense_variant	35/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

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:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251432

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000607

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:

0.000229

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000313

AC:

458

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000361

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000309

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Marfan syndrome

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 07, 2022	This variant has been reported in the literature in several individuals with a clinical suspicion or diagnosis of Marfan syndrome (Selected publications: Comeglio 2001 PMID: 11748851, Comeglio 2007 PMID: 17657824, Stheneur 2009 PMID: 19293843, Arnaud 2017 PMID: 27582083). This variant is present in gnomAD (Highest reported MAF: 0.2% [31/15280]; https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3) and in ClinVar (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, a different variant at the same amino acid position (p.Pro1424Ser) has been previously reported in association with disease (Arbustini 2005 PMID: 16222657; Piqueras-Flores 2019 PMID: 31053375). However, because of this variant's high frequency in the general population, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 17, 2019	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2022	Reported in an unaffected relative in the published literature and observed in unaffected relatives referred for testing at GeneDx (Howarth et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1 related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 9399842, 25812041, 25637381, 28655553, 14695540, 19161152, 19293843, 11748851, 23506379, 24941995, 26621581, 25944730, 27647783, 27582083, 17627385, 27153395, 31098894, 12938084, 17657824, 31211626, 27535533) -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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	Ambry Genetics	May 25, 2018	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	Illumina Laboratory Services, Illumina	Jun 17, 2019	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 25, 2022	This variant has been reported in the literature in at least 11 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom were reported as compound heterozygotes (Collod-Beroud 1998 PMID:9399842, Comeglio 2001 PMID:11748851, Biggin 2004 PMID:14695540, Comeglio 2007 PMID:17657824, Howarth 2007 PMID:17627385, Stheneur 2009 PMID:19293843, Turner 2009 PMID:19161152, Callier 2013 PMID:23506379, Arnaud 2017 PMID:27582083, Mattessi 2018 PMID:28655553). This variant is present in 0.2% (31/15280) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3). Of note, the frequency of this variant is inconsistent with the expected incidence of this condition and several entries in ClinVar have noted this information in their classification (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. A Likely Pathogenic variant at the same amino acid position (p.Pro1424Ser) has been previously reported (Arbustini 2005 PMID:16222657; Piqueras-Flores 2019 PMID:31053375). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251532 control chromosomes. The observed variant frequency is approximately 1.8 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.4270C>G has been reported in the literature in individuals affected with features of or undergoing testing for Marfan Syndrome/familial thoracic aortic aneurysms and dissections. These data do not allow any conclusion about variant significance. 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: 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 27153395, 26787436). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=11, B/LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 21, 2013	The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant . -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta

Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 20, 2016

- -

Stiff skin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 17, 2019

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Weill-Marchesani syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 17, 2019

Geleophysic dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 17, 2019

Acromicric dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 17, 2019

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Ectopia lentis 1, isolated, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 17, 2019

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.61

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Vest4

0.61

MVP

0.93

MPC

0.56

ClinPred

0.48

GERP RS

5.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over