rs191989961

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000138.5(FBN1):c.4001G>A(p.Gly1334Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 6.21

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 Benign. Variant got -10 ACMG points.

PM1

In a disulfide_bond (size 13) in uniprot entity FBN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000138.5

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=0.044210315).

BP6

Variant 15-48474614-C-T is Benign according to our data. Variant chr15-48474614-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000131 (20/152248) while in subpopulation AMR AF= 0.00111 (17/15286). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.4001G>A	p.Gly1334Asp	missense_variant	Exon 33 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.4001G>A	p.Gly1334Asp	missense_variant	Exon 32 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.4001G>A	p.Gly1334Asp	missense_variant	Exon 33 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251238

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000131

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.000268

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly1334Asp variant in FBN1 has been identified by our laboratory in 2 indi viduals with features of Marfan syndrome and segregated with disease in 3 affect ed relatives. This variant has been identified in 1/11566 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191989961). Glycine (Gly) at position 1334 is not conserved in mammals or evo lutionarily distant species and >20 mammals/species carry an aspartic acid (Asp) , raising the possibility that this change may be tolerated. Additional computat ional prediction tools suggest that this variant may not impact the protein, tho ugh this information is not predictive enough to rule out pathogenicity. In summ ary, due to conflicting data, the clinical significance of the p.Gly1334Asp vari ant is uncertain. -

May 13, 2019

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.4001G>A (p.Gly1334Asp) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Missense mutations located within the conserved residues of the EGF consensus sequence are listed among the criteria for a causal FBN1 mutation when identified as de novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (PMID: 20591885). 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 8e-06 in 251238 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4001G>A has been reported in the literature in individuals with Marfan Syndrome-like features but no definitive diagnosis (Delio_2015, Lerner-Ellis_2014). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. Co-occurrences with pathogenic variants have been reported (FBN1 c.5788+1G>A; FBN1 c.6658C>T, p.Arg2220*; LabCorp). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Marfan syndrome

Uncertain:2

Sep 23, 2024

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 glycine with aspartic acid at codon 1334 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 four individuals with Marfan syndrome-like features (PMID: 24793577, 26214305). Two of these individuals were twin siblings who were also affected with multiple other congenital abnormalities (PMID: 26214305). This variant has been observed to co-occur with another FBN1 variant (c.1006T>C, p.Cys336Arg) in an adolescent individual affected with Marfan syndrome ( doi:10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2052). This variant has been identified in 2/251238 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. -

Jan 29, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited c.4001G>A (p.Gly1334Asp) variant identified in the FBN1 gene substitutes a moderately conserved Glycine for Aspartic Acid at amino acid 1334/2872 (coding exon 33/66). This variant is found in 20 heterozygotes and 0 homozygotes in gnomAD(v3.1) with an allele frequency of 1.32e-4. In silico algorithms predict this variant to be Neutral (Provean; score: 3.75) and Tolerated (SIFT; score: 1.00) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:42345), including a submission by one clinical lab in which this variant was identified in a family with features of Marfan syndrome. The p.Gly1334Asp variant identified here has also been reported in the literature in a family with Marfan syndrome like features, ticks, possible Tourette Syndrome, speech delay and fine motor delay [PMID:26214305]. The p.Gly1334 residue is within one of the EGF-like calcium binding domains of FBN1 (UniProtKB:P35555). While it has been observed in affected individuals in the literature, the presence of 20 heterozygotes in gnomAD(v3.1) is higher than expected for autosomal dominant Marfan Syndrome. Given this, the inherited c.4001G>A (p.Gly1334Asp) variant identified in the FBN1 gene is reported as a Variant of Uncertain Significance. -

FBN1-related disorder

Uncertain:2

Jan 15, 2020

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.4001G>A (p.Gly1334Asp) variant is a missense variant that has been reported in a pair of male twins with Marfan-like features, both of whom also had other medical issues (Delio et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000058 in the Latino population of the Genome Aggregation Database though this is based on two alleles in a region of good sequence coverage, so the variant is presumed to be rare. Based on the limited evidence, the p.Gly1334Asp variant is classified as a variant of unknown significance for FBN1-related disorders. -

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.4001G>A variant is predicted to result in the amino acid substitution p.Gly1334Asp. This variant has been reported in two unrelated individuals with Marfan syndrome-like features (Table S6, IDs 7 and 32, Lerner-Ellis et al. 2014. PubMed ID: 24793577). It has also been reported in a set of male twins with Marfan syndrome-like features, multiple congenital anomalies, focal segmental glomerulosclerosis, ticks, speech delay, fine motor delay and possible Tourette syndrome (Table 2, Table S4, Delio et al. 2015. PubMed ID: 26214305). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:1

Feb 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 02, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Nov 09, 2021

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 24, 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

0.075

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.69

PrimateAI

Benign

0.42

PROVEAN

Benign

3.8

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.23

MVP

0.33

MPC

0.65

ClinPred

0.48

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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