rs376119827

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000138.5(FBN1):c.8232G>C(p.Gln2744His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q2744Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.530

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 -5 ACMG points.

PP2

Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.17460614).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.8232G>C	p.Gln2744His	missense_variant	Exon 66 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.8232G>C	p.Gln2744His	missense_variant	Exon 65 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.8232G>C	p.Gln2744His	missense_variant	Exon 66 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250796

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 27, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a proband with a history of a carotid artery dissection, borderline aortic root aneurysm, and pneumothorax (Overwater et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 457269; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29907982) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Marfan syndrome

Uncertain:2

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with histidine at codon 2744 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 reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection and/or bicuspid aortic valve (PMID: 28659821, 29907982). This variant has been identified in 3/250796 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. -

Apr 29, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1 c.8232G>C has been identified in a single individual with features of an FBN1-related condition. This FBN1 variant(rs376119827) is rare (<0.1%) in a large population dataset (gnomAD: 3/250796 total alleles; 0.001196%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be tolerated and the glutamine residue at this position is not highly evolutionarily conserved across the species assessed. We consider the clinical significance of FBN1 c.8232G>C to be uncertain at this time. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2

Mar 20, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q2744H variant (also known as c.8232G>C), located in coding exon 65 of the FBN1 gene, results from a G to C substitution at nucleotide position 8232. The glutamine at codon 2744 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a subject with carotid artery dissection, aortic aneurysm and pneumothorax (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Feb 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Uncertain:1

Sep 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.8232G>C (p.Gln2744His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250796 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8232G>C has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual affected with suspected heritable thoracic aortic disorders (example, Overwater_2018) and also in an individual undergoing candidate gene resequencing In a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort (example, Gillis_2017). These report(s) 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain 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:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.87

Eigen

Benign

-0.038

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.54

M_CAP

Benign

0.045

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.58

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.29

REVEL

Benign

0.29

Sift

Benign

0.11

Sift4G

Benign

0.28

Vest4

0.13

MutPred

0.34

Gain of glycosylation at S2739 (P = 0.1331);

MVP

0.72

MPC

0.57

ClinPred

0.11

GERP RS

3.1

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

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