rs191989961

chr15-48474614-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 6.21

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.044210315).
• 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4001G>A	p.Gly1334Asp	missense_variant	33/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4001G>A	p.Gly1334Asp	missense_variant	32/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4001G>A	p.Gly1334Asp	missense_variant	33/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152130 Hom.: 0 Cov.: 32

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: 2 AN: 251238 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135782

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: 5 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

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: 20 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74436

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: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 13, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2019	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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 29, 2021	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. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 02, 2023

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. -

FBN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2020

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. -

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

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	3.8	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.23
MVP		0.33
MPC		0.65
ClinPred		0.48	T
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

Other links and lift over

dbSNP: rs191989961; hg19: chr15-48766811;